BCG Vaccination

CHAPTER 14

BCG Vaccination Moshe Tishler1

Department of Medicine B, Asaf Harofe Medical Center, Zrifin, Israel Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel 1 Corresponding Author: [email protected]

1 INTRODUCTION Although vaccination is a very effective tool to prevent infectious diseases, it has a powerful stimulation on the immune system, which has created some fears concerning its role in creating autoimmune phenomena. This issue has been discussed extensively in the literature for the past decade, both in case reports and in reviews. The relationship between vaccination and autoimmunity is bidirectional. On the one hand, vaccination can prevent autoimmune diseases that might be triggered by infectious agents. On the other hand, many case reports and clinical studies, most of them observational, have described both post-vaccination autoimmune phenomena and full-blown diseases. Establishing a causal relationship between vaccination and autoimmune disease induction is difficult to prove in humans because the need to perform large complex and expensive epidemiological studies will limit their availability.1 Moreover, the criteria for such causality are not well defined, because safety cannot be measured directly and such a link can be suspected only indirectly by a temporal relationship of these two events.2 Bacillus Calmette–Gue´rin (BCG) vaccine was derived from an attenuated strain of Mycobacterium bovis, and was first administered to humans in 1921. This vaccine, which is almost one century old, remains today the only available vaccine against tuberculosis (TB). It is routinely administered to infants in many countries worldwide with high TB prevalence and to health care employees in endemic areas. This vaccine is also used intravesically as an adjuvant treatment for intermediate- and high-risk superficial bladder cancer with impressive efficacy. In this chapter the relationship between BCG vaccination, BCG immunotherapy, and autoimmunity is discussed. Infection and Autoimmunity http://dx.doi.org/10.1016/B978-0-444-63269-2.00017-9

© 2015 Elsevier B.V. All rights reserved.

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2 MYCOBACTERIA AND AUTOIMMUNITY Mycobacteria have long been found to be immunogenic, and many autoantibodies can be detected with high frequency in patients infected by mycobacteria.3 These included ds-DNA, Sm, RNP, Ro, IgM-ACA, and b2 glycoprotein-1, many of which were above the normal serum concentrations. A similarity between human and mycobacterial antigens has been proven both in humoral and cellular mechanisms. Monoclonal anti-DNA antibodies derived from both patients and mice with systemic lupus erythematosus (SLE) were found to bind to three glycoproteins extracted from mycobacterial cell walls.4 The inhibition of such a binding could be inhibited by the prior incubation of antibodies with glycolipid antigens and with anti-SS DNA, thus indicating a sharing of common antigens between human tissue and mycobacteria. Studies performed in the early 1980s in a model of rat with adjuvant arthritis have found a T-cell clone specific for Mycobacterium tuberculosis, which was arthritogenic.5 There is ample evidence which suggests that TB reactive T-cells can potentially recognize self-antigens. This evidence came from both animal models and affected individuals with arthritis. In a model of adjuvant arthritis in rat cross antigenicity between M. tuberculosis and human cartilage, proteoglycans have been demonstrated.6 Furthermore, T-cells responding to the 65-kDa antigen of M. tuberculosis have been shown to be present in the synovial fluid of patients with early chronic arthritis.7 The immunogenic effect of mycobacteria has not been limited to the strain of the bacteria or to the adjuvant arthritis model. In a pre-diabetic non-obese diabetic (NOD) mice model, a single injected dose of M. bovis resulted in the prevention of type 1 diabetes but the appearance of a systemic autoimmune disease similar to SLE manifested by hemolytic anemia, sialadenitis, and glomerulonephritis.8 Furthermore, a proof-of-concept randomized controlled study done in adults with type 1 diabetes who received BCG vaccine has shown transient elevation of c-peptide, which suggests that BCG stimulates host innate immunity.9 Sarcoidosis is another granulomatous disorder of unknown etiology in which autoimmunity probably plays a role. A recent hypothesis suggests that in genetically different individuals the same mycobacterial heat shock proteins may induce different immune responses. This hypothesis is supported by the fact that in epidemiological worldwide studies the distribution of TB is approximately opposite to that of sarcoidosis.10

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This molecular mimicry between mycobacteria and self-antigens that causes autoimmune responses can be used as a conceptual basis for a potential use of a number of M. tuberculosis-specific T-cell epitopes as potential vaccines for therapeutic purposes.11

3 BCG IN CLINICAL PRACTICE BCG is used both as a vaccine for the prevention of TB, and as intravesical instillation for treatment of superficial bladder cancer. BCG vaccination is routinely used in children worldwide, especially in countries with endemic TB. Reported side effects of vaccination are extremely uncommon. In a study that followed 5.5 million vaccinated children in six European countries, the incidence of systemic side effects was 2.8 cases per million.12 These systemic side effects were mainly disseminated to organs (bones, joints, liver, meninges) via lymphatic or blood circulation. Miliary spread was exceedingly rare and was seen only in immunocompromised children. Another complication reported in immunocompetent children is osteoarticular infection with M. bovis. The prevalence of such infection varies across Europe and is high in Scandinavian countries (6.4/100,000) while very low in France (0.39/1,000,000).13 The explanation of this variation can be explained by many factors, such as age of vaccination, vaccine preparation, and different manufactures. Osteoarticular complications usually occur 20 months after vaccination (range 3–60 months), and the lower limbs are selectively affected with a typical solitary lesion in the metaphyses of long bones. Given that M. bovis strains are usually resistant to a single-drug regimen, combination therapy with rifampin, isoniazide, and ethambutol is given for the first 2 months, followed by rifampin and isoniazide for another 10 months.14 A small number of other complications, such as aseptic polyarthritis, sarcoidosis, dermatomyositis, and anterior uveitis,15–18 have been reported as case reports associated with BCG vaccination.

4 INTRAVESICAL BCG INSTILLATION Intravesical instillation of BCG has been used successfully since 1976. This method of treatment is given for superficial bladder carcinoma and does not destroy tumor cells directly, but rather increases local immune response

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against the tumor. Recently updated guidelines of the European Association of Urology recommended that patients with non-muscle-invasive urothelial bladder carcinoma with intermediate- and high-risk tumor should be treated with BCG instillation for 1–3 years accordingly.19 In most patients, treatment has no serious side effects, and the most common adverse effects such as malaise, low-grade fever, cystitis, and hematuria are self-limited. More serious side effects that have been reported include rash, renal and prostatic abscesses, epididymitis, pneumonitis, hepatitis, and osteoarticular side effects.20 Also, various musculoskeletal side effects have been reported, with a prevalence ranging from 0.5% to 1%.13,21 Most reviews have shown that patients’ complaints were due to arthralgia, but arthritis has not been common. Arthritis secondary to intravesical BCG instillation has been mainly documented as case reports. Two reviews published in 2006 reported 43 and 59 patients, respectively,11,20 who were compared to patients with a classic pattern of reactive arthritis. A recent article reviewed 73 papers present in the world literature with a total of 112 patients, but it focused only on 61 papers with a total of 89 patients suitable for evaluation.21 Most of the reported cases (80%) were males with a mean age of 62.1  10.8 years, and the onset of arthritis from the last instillation was 14 days on average. The clinical manifestation of arthritis was symmetrical polyarticular in about 55%, oligoarticular in about 33%, and monoarticular in 8% of patients. Although polyarthritis was symmetric in half of the reported cases in those with oligoarthritis, it was symmetric in only 33% of reported cases. The most frequently affected joints were those of the lower limbs, mainly the knees, ankles, and feet. When arthritis presented as monoarticular disease, the only involved joints were knees and ankles, whereas in the polyarticular presentation, the small joints of hands and feet were more frequently affected. Neither the duration of the arthritis nor the levels of inflammatory markers were significantly related to the number, size, or site of the involved joints. Spinal pain was present in 8% of reported cases and bilateral sacroiliitis in 9% of patients. The mean duration of symptoms in affected patients was about 2 months, and more than 90% of patients recovered completely within 6 months. The prevalence of human leukocyte antigen (HLA) B27 is reported in about 50% of affected patients and was more prevalent in those with polyarticular involvement. The erythrocyte sedimentation rate (ESR) was reported to be elevated in more than 90% of cases, synovial cultures were negative in all patients and radiographic evaluation usually revealed no specific abnormalities.

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Treatment regimen, according to reported cases, included mainly NSAIDs; a minority of patients with severe polyarthritis were treated with corticosteroids as well. Overall, arthritis has a favorable course, and pharmacologic treatment is effective in nearly all cases.26

5 BCG AND ARTHRITIS: MECHANISM OF ACTION The exact mechanism of BCG-induced arthritis is not clear and well defined. Studies of animals have shown that the antineoplastic effect of BCG requires an intact host immune system.22 Clinical and laboratory evidence suggests that the antitumor activity of the vaccine seems to be confined to the site of administration. BCG does not act by the direct killing of the neoplastic cells, but rather by stimulating local inflammatory response and local cytokine production. It has been shown that, following sequential instillation of BCG into the bladder, large quantities of various cytokines can be detected in the urine, including IL-1b, IL-2, IL-6, IL-8, IL-10, TNF-a, IFN-g, and soluble ICAM-1.23 Although response has been reported to be heterogeneous between patients at baseline, the concentration of the various cytokines are increased with repeated BCG instillation. The most likely mechanism involved in BCG arthritis is that of molecular mimicry, as suggested by the shared homology between mycobacterial heat shock protein 65 and cartilage proteoglycans.6 Moreover, serial biopsies obtained during treatment revealed induction of strong HLA-DR expression by urothelial cells that persisted for several months after completion of therapy.24 It is presumed that penetration of the bacteria or bacterial antigens through the wall of the inflamed bladder tissue into the circulation can generate a systemic immune response with the joints as a target. An attack on the joints can take place in genetically susceptible individuals such as those with specific HLA antigens. Such genetic susceptibility has been found in subjects positive to HLA B27 antigen who were treated with BCG instillation.22 Indeed, more than 50% of patients with arthritis after BCG therapy were carrying the HLA B27 antigen, particularly those with more severe polyarthritis. The effect of generating an effect on a host organism from within has been given the name “Trojan horse”25 and is not unique to BCG vaccination, but rather to a large number of autoimmune phenomena occurring after vaccination.

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6 CONCLUSION BCG immunization has proved to be a powerful tool both in preventing TB in endemic areas and as a treatment for superficial bladder carcinoma when given intravesically. Side effects of such immunization using both methods have been infrequently recorded and are usually mild and self-limited. Nevertheless, immunization, especially by intravesical instillation, can act as “a double-edged sword”27 and trigger autoimmune phenomena and even a full-blown autoimmune disease. This link between mycobacteria and autoimmunity is probably a consequence of molecular mimicry, although genetic and environmental factors might play an important role as well.

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14. Kroger L, Korppi M, Brander E, Kroger H, Wasz-Hockert O, Backman A, et al. Osteitis caused by BCG vaccination a retrospective analysis of 222 cases. J Infect Dis 1995;172:574–6. 15. Koduli VR, Clague BB. Arthritis after BCG vaccine in a healthy woman. J Intern Med 1998;244:183–4. 16. Osborne G, Mallon E, Mayon S. Juvenile sarcoidosis after BCG vaccination. J Am Acad Dermatol 2003;48:99–102. 17. Kass E, Straume S, Munthe E. Dermatomyositis after BCG vaccination. Lancet 1978;1:772. 18. Spratt A, Key T, Vivian AJ. Chronic anterior uveitis following BCG vaccination: molecular mimicry in action? J Pediatr Ophtalmol Strabismus 2008;45:252–3. 19. Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Comperat E, et al. EAU guidelines of non-muscle invasive urothelial carcinoma of bladder: update 2013. EUR Urol 2013;64:639–53. 20. Sylvester RJ, van der Meijden AP, Lamom DL, Intraversical BCG reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964–70. 21. Lamm D, Stogdill V, Stogdill B, Crispen R. Complications of immunotherapy in 1278 patients with bladder cancer. J Urol 1986;135:272–4. 22. Tinazzi E, Ficarra V, Simeoni S, Artibani W, Lunardi C. Reactive arthritis following BCG immune therapy for urinary bladder carcinoma: a systematic review. Rheumatol Int 2006;26:481–8. 23. Jackson AN, Alexandroff AB, Kelly RW, Shibinska A, Esuvaranathan K, et al. Changes in urinary cytokines and soluble intracellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after BCG immunotherapy. Clin Exp Immunol 1995;991:369–75. 24. Prescott S, James K, Busuttil A, Hargreave TB, Chrisholm GD, Smyth JF. HLA-DR expression by high grade superficial bladder cancer treated with BCG. Br J Urol 1989;63:264–9. 25. Aron-Maor A, Shoenfeld Y. BCG immunization and the “Trojan Horse” phenomenon of vaccination. Clin Rheumatol 2003;22:6–7. 26. Bernini L, Manzini CU, Giuggioli D, Sebastian M, Ferri C. Reactive arthritis induced by intravesical BCG therapy for bladder cancer: our clinical experience and systematic review of the literature. Autoimmun Rev 2013;12:1150–9. 27. Shoenfeld Y, Aron-Maor A, Tania A, Eherenfeld M. BCG and autoimmunity: another two edged sword. J Autoimmun 2001;16:235–40.