Sjögren's-like syndrome following intravesical bacillus Calmette-Guérin immunotherapy.

Immunotherapy with Calmette-Guérin bacillus (BCG) is effective in the treatment of superficial bladder cancer. Although generally considered to be safe and well tolerated, it is associated with several systemic side effects (1Lamm D.L. Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer.Clin Infect Dis. 2000; 31: S86-S90Crossref PubMed Scopus (214) Google Scholar, 2Elkabani M. Greene J.N. Vincent A.L. Van Hook S. Sandin R.L. Disseminated Mycobacterium bovis after intravesical bacillus Calmette-Guerin treatment for bladder cancer.Cancer Control. 2000; 7: 476-481PubMed Google Scholar, 3Schattner A. Gilad A. Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy.J Intern Med. 2002; 251: 272-277Crossref PubMed Scopus (22) Google Scholar, 4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar). However, there is debate over whether these systemic complications represent a hypersensitivity response or an ongoing infection. We report a patient who developed a Sjögren's-like syndrome after receiving intravesical BCG immunotherapy for bladder cancer.A 59-year-old woman who had localized, superficial transitional cell carcinoma of the bladder was treated with cystoscopic resection followed by intravesical BCG immunotherapy. Two 6-week courses of intravesical BCG were planned. Several weeks after the first course of treatment, she developed symptoms of keratoconjunctivitis sicca, oral dryness, and painful salivary gland enlargement. Physical examination revealed small cervical lymph nodes and mild enlargement of the parotid and submandibular glands. Routine laboratory data were unremarkable, except for an elevated erythrocyte sedimentation rate (40 mm/h). Serum proteinogram showed an increase in α-2 globulin levels without hypergammaglobulinemia. Serological tests for hepatitis C, rheumatoid factor, antinuclear antibody, SS-A, SS-B, and human leukocyte antigen B27 (HLA-B27) were negative. Chest radiograph was normal. Intradermal tuberculin test was positive.The presence of dry eyes was confirmed by a positive Schirmer's tear test and abnormal tear film breakup time. Xerostomia was confirmed by salivary gland scintigraphy. A computed tomographic (CT) scan of the neck showed small cervical lymph nodes in the jugulocarotid chain and signs of mild sialadenitis, which was most obvious in the parotid and submandibular glands. Abdominal CT scan was normal. Submandibular gland biopsy specimen revealed lymphoplasmacytoid sialadenitis without granulomas. Biopsy of a cervical lymph node revealed hyperplasia of monocytoid cells and sinusoidal hyperplasia; the immunohistochemical study excluded malignant lymphoproliferative disorder. There were no acid-fast bacilli in both specimens by cultures and polymerase chain reaction analysis.The second course of BCG immunotherapy was suspended, and the patient received nonsteroidal anti-inflammatory drugs and treatment for sicca symptoms, which led to marked improvement and rapid regression of the salivary gland enlargement and the cervical lymph nodes. After 9 months without therapy, she remained well, without fever or constitutional symptoms and with a normal erythrocyte sedimentation rate. No lymphadenopathies or salivary gland enlargement were detected on physical examination.We believe that BCG immunotherapy led to the development of a Sjögren’s-like syndrome in this patient. Serum autoantibodies were negative and most known conditions that can mimic the clinical picture of Sjögren's syndrome were ruled out. There was lymphoplasmacytoid sialadenitis without granulomas, and there were no acid-fast bacilli. Moreover, the patient responded dramatically to anti-inflammatory therapy. These findings support the notion of a hypersensitivity response triggered by BCG instillation as the most likely pathogenic mechanism of this complication. In this sense, mycobacteria have been proven to be immunogenic. Indeed, cross-reactivity between mycobacterial antigens and cartilage proteins has been shown (6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar).An increasing number of cases of autoimmune phenomena, mainly rheumatic manifestations, developing after BCG immunotherapy has recently been reported (3Schattner A. Gilad A. Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy.J Intern Med. 2002; 251: 272-277Crossref PubMed Scopus (22) Google Scholar, 4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar). The development of inflammatory aseptic arthritis in patients treated with intravesical BCG instillations is a rare but well-known complication that has been explored extensively in recent years (4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). In these patients, a cytotoxic response is observed, with the activation of both CD4+ and CD8+ T cells, triggered by BCG instillation (8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). Thereafter, these T cells could cross-react with self-antigens by a molecular mimicry mechanism (4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). A member of the heat shock protein (HSP) family, HSP-65 kDa or HSP-60 kDa, may be involved (4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). This complication occurs predominantly in patients with a genetic predisposition (60% of the patients are HLA-B27 positive) (5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar). Thus, an immune response initiated by BCG instillation might be enhanced by cross-reactivity with the patient's self-HSP, presented by the HLA-B27 molecule. Synovial biopsies in patients with reactive arthritis after BCG immunotherapy show lymphoplasmacytoid synovitis (7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar). In our patient, HLA-B27 was negative, but a biopsy revealed lymphoplasmacytoid sialadenitis without granulomas.Additional support for the hypersensitivity hypothesis in this patient comes from animal models. A single dose of Mycobacterium bovis injected to nonobese diabetic mice precipitated a systemic lupus erythematosus–like syndrome (9Baxter A.G. Horsfall A.C. Healey D. et al.Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice.Immunology. 1994; 83: 227-231PubMed Google Scholar). Furthermore, treatment of NZB/NZW f1 hybrid mice with an M. bovis strain of BCG was found to accelerate autoimmune disease (10Engelman E.G. Sonnenfield G. Dauphinee M. Treatment of NZB/NZW f1 hybrid mice with Mycobacterium bovis strain of BCG or type II interferon preparations accelerates autoimmune disease.Arthritis Rheum. 1981; 323: 1381-1387Google Scholar).In conclusion, a Sjögren's-like syndrome may occur following intravesical BCG instillation for bladder cancer. This case and others (1Lamm D.L. Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer.Clin Infect Dis. 2000; 31: S86-S90Crossref PubMed Scopus (214) Google Scholar, 2Elkabani M. Greene J.N. Vincent A.L. Van Hook S. Sandin R.L. Disseminated Mycobacterium bovis after intravesical bacillus Calmette-Guerin treatment for bladder cancer.Cancer Control. 2000; 7: 476-481PubMed Google Scholar, 3Schattner A. Gilad A. Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy.J Intern Med. 2002; 251: 272-277Crossref PubMed Scopus (22) Google Scholar, 4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar) support the link between BCG immunotherapy and autoimmunity. Immunotherapy with Calmette-Guérin bacillus (BCG) is effective in the treatment of superficial bladder cancer. Although generally considered to be safe and well tolerated, it is associated with several systemic side effects (1Lamm D.L. Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer.Clin Infect Dis. 2000; 31: S86-S90Crossref PubMed Scopus (214) Google Scholar, 2Elkabani M. Greene J.N. Vincent A.L. Van Hook S. Sandin R.L. Disseminated Mycobacterium bovis after intravesical bacillus Calmette-Guerin treatment for bladder cancer.Cancer Control. 2000; 7: 476-481PubMed Google Scholar, 3Schattner A. Gilad A. Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy.J Intern Med. 2002; 251: 272-277Crossref PubMed Scopus (22) Google Scholar, 4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar). However, there is debate over whether these systemic complications represent a hypersensitivity response or an ongoing infection. We report a patient who developed a Sjögren's-like syndrome after receiving intravesical BCG immunotherapy for bladder cancer. A 59-year-old woman who had localized, superficial transitional cell carcinoma of the bladder was treated with cystoscopic resection followed by intravesical BCG immunotherapy. Two 6-week courses of intravesical BCG were planned. Several weeks after the first course of treatment, she developed symptoms of keratoconjunctivitis sicca, oral dryness, and painful salivary gland enlargement. Physical examination revealed small cervical lymph nodes and mild enlargement of the parotid and submandibular glands. Routine laboratory data were unremarkable, except for an elevated erythrocyte sedimentation rate (40 mm/h). Serum proteinogram showed an increase in α-2 globulin levels without hypergammaglobulinemia. Serological tests for hepatitis C, rheumatoid factor, antinuclear antibody, SS-A, SS-B, and human leukocyte antigen B27 (HLA-B27) were negative. Chest radiograph was normal. Intradermal tuberculin test was positive. The presence of dry eyes was confirmed by a positive Schirmer's tear test and abnormal tear film breakup time. Xerostomia was confirmed by salivary gland scintigraphy. A computed tomographic (CT) scan of the neck showed small cervical lymph nodes in the jugulocarotid chain and signs of mild sialadenitis, which was most obvious in the parotid and submandibular glands. Abdominal CT scan was normal. Submandibular gland biopsy specimen revealed lymphoplasmacytoid sialadenitis without granulomas. Biopsy of a cervical lymph node revealed hyperplasia of monocytoid cells and sinusoidal hyperplasia; the immunohistochemical study excluded malignant lymphoproliferative disorder. There were no acid-fast bacilli in both specimens by cultures and polymerase chain reaction analysis. The second course of BCG immunotherapy was suspended, and the patient received nonsteroidal anti-inflammatory drugs and treatment for sicca symptoms, which led to marked improvement and rapid regression of the salivary gland enlargement and the cervical lymph nodes. After 9 months without therapy, she remained well, without fever or constitutional symptoms and with a normal erythrocyte sedimentation rate. No lymphadenopathies or salivary gland enlargement were detected on physical examination. We believe that BCG immunotherapy led to the development of a Sjögren’s-like syndrome in this patient. Serum autoantibodies were negative and most known conditions that can mimic the clinical picture of Sjögren's syndrome were ruled out. There was lymphoplasmacytoid sialadenitis without granulomas, and there were no acid-fast bacilli. Moreover, the patient responded dramatically to anti-inflammatory therapy. These findings support the notion of a hypersensitivity response triggered by BCG instillation as the most likely pathogenic mechanism of this complication. In this sense, mycobacteria have been proven to be immunogenic. Indeed, cross-reactivity between mycobacterial antigens and cartilage proteins has been shown (6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar). An increasing number of cases of autoimmune phenomena, mainly rheumatic manifestations, developing after BCG immunotherapy has recently been reported (3Schattner A. Gilad A. Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy.J Intern Med. 2002; 251: 272-277Crossref PubMed Scopus (22) Google Scholar, 4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar). The development of inflammatory aseptic arthritis in patients treated with intravesical BCG instillations is a rare but well-known complication that has been explored extensively in recent years (4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). In these patients, a cytotoxic response is observed, with the activation of both CD4+ and CD8+ T cells, triggered by BCG instillation (8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). Thereafter, these T cells could cross-react with self-antigens by a molecular mimicry mechanism (4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). A member of the heat shock protein (HSP) family, HSP-65 kDa or HSP-60 kDa, may be involved (4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar). This complication occurs predominantly in patients with a genetic predisposition (60% of the patients are HLA-B27 positive) (5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar). Thus, an immune response initiated by BCG instillation might be enhanced by cross-reactivity with the patient's self-HSP, presented by the HLA-B27 molecule. Synovial biopsies in patients with reactive arthritis after BCG immunotherapy show lymphoplasmacytoid synovitis (7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar). In our patient, HLA-B27 was negative, but a biopsy revealed lymphoplasmacytoid sialadenitis without granulomas. Additional support for the hypersensitivity hypothesis in this patient comes from animal models. A single dose of Mycobacterium bovis injected to nonobese diabetic mice precipitated a systemic lupus erythematosus–like syndrome (9Baxter A.G. Horsfall A.C. Healey D. et al.Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice.Immunology. 1994; 83: 227-231PubMed Google Scholar). Furthermore, treatment of NZB/NZW f1 hybrid mice with an M. bovis strain of BCG was found to accelerate autoimmune disease (10Engelman E.G. Sonnenfield G. Dauphinee M. Treatment of NZB/NZW f1 hybrid mice with Mycobacterium bovis strain of BCG or type II interferon preparations accelerates autoimmune disease.Arthritis Rheum. 1981; 323: 1381-1387Google Scholar). In conclusion, a Sjögren's-like syndrome may occur following intravesical BCG instillation for bladder cancer. This case and others (1Lamm D.L. Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer.Clin Infect Dis. 2000; 31: S86-S90Crossref PubMed Scopus (214) Google Scholar, 2Elkabani M. Greene J.N. Vincent A.L. Van Hook S. Sandin R.L. Disseminated Mycobacterium bovis after intravesical bacillus Calmette-Guerin treatment for bladder cancer.Cancer Control. 2000; 7: 476-481PubMed Google Scholar, 3Schattner A. Gilad A. Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy.J Intern Med. 2002; 251: 272-277Crossref PubMed Scopus (22) Google Scholar, 4Buchs N. Chevrel G. Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis.J Rheumatol. 1998; 25: 1662-1665PubMed Google Scholar, 5Mas A.J. Romera M. Valverde Garcia J. Articular manifestations after the administration of intravesical BCG.Joint Bone Spine. 2002; 69: 92-98Crossref PubMed Scopus (22) Google Scholar, 6Shoenfeld Y. Aron-Maor A. Tanai A. Ehrenfeld M. BCG and autoimmunity: another two-edged sword.J Autoimmun. 2001; 16: 235-240Crossref PubMed Scopus (50) Google Scholar, 7Smith M.D. Chandran G. Parker A. et al.Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy.J Rheumatol. 1997; 24: 752-758PubMed Google Scholar, 8Bartolomé Pacheco M.J. Martinez Taboada V.M. Blanco R. Rodriguez Valverde V. Valle J.I. López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.Rheumatology. 2002; 41: 1119-1125Crossref PubMed Google Scholar) support the link between BCG immunotherapy and autoimmunity.