Introduction

In the United States, urinary bladder cancer is the cause of 13,000 deaths each year: more than 60,000 new cases are expected to appear in 2004, making it the fourth most common cancer among men and the tenth among women [1]. The majority of these tumors are transitional cell carcinoma (TCC) and are typically superficial [carcinoma in situ (CIS) or Ta and T1 cancer] [2]. The overall 10-year survival rate of patients with superficial disease is approximately 80%, ranging from 50% to more than 95%, depending on the grade of the tumor [3, 4]. A recurrence as high as 40–80% in patients affected by TCC has been reported and approximately 20% of tumors initially diagnosed as superficial will progress to invade the muscle or become metastatic [5, 6]. Complete transurethral resection (TURBT) of superficial disease followed by intravesical immunotherapy in patients at risk for recurrence or progression seems to improve the outcome [7].

Since 1976, when Morales first described the antitumor effects of intravesical administration of Mycobacterium bovis Bacillus Calmette-Guerin (BCG) [8], local immunotherapy has been used in the treatment of patients with superficial bladder carcinoma with efficacy and safety [9]. Intravesical therapy is commonly used as a prophilactic treatment to prevent recurrence of the disease, and as a therapeutic treatment to eliminate residual small volume disease and CIS and therefore to prevent the progression of the tumor. Indeed, this local immunotherapy can effectively treat more than 70% of CIS patients without cystectomy [10–12] and is efficacious against T1 grade 3 bladder cancer, which is thought to have high local progression potential [13]. Long-term studies have documented benefits in terms of decreased recurrence rate, decreased progression rate, reduced cystectomy and also improved survival [4, 5, 7, 14]. Despite the efficacy, there is still a group of patients nonresponsive to BCG therapy, requiring total cystectomy [15]. Recently, Satoh et al. [16] have studied the clinical characteristics of 152 patients with bladder cancer, with particular attention to the variables that affect efficacy of intravesical therapy and relapse of the disease. Only proteinuria adversely affects the efficacy of intravesical BCG therapy and may be useful in the identification of patients at high risk for tumor recurrence.

BCG immunotherapy is generally well tolerated and the vast majority of patients do not present any side effect. Indeed, only 5% of patients have mild and short-lived clinical manifestations, such as malaise, low-grade fever, cystitis and hematuria. The rare severe and long-lasting complications of BCG therapy are characterized by localized or systemic diseases, such as local inflammatory reaction, epididimitis, renal abscess, pneumonitis, sepsis and rash [17].

We recently observed the development of arthralgia, evolving in typical arthritis in the left knee with joint effusion, tenderness and redness in a 68-year-old man who received a 6-week course of once-weekly intravesical BCG instillation for high-risk superficial bladder carcinoma [T1G3 associated with CIS]. The arthritis was resolved with nonsteroidal anti-inflammatory drugs (NSAIDs) therapy and the discontinuation of BCG therapy [18]. We therefore decided to critically analyze the cases of arthralgias and arthritis following BCG immunotherapy, reported in the literature.

Materials and methods

The systematic review of the literature was performed using MEDLINE. In detail, the electronic search was conducted using the following key words: “BCG immunotherapy” and “Arthritis, arthralgias and BCG immunotherapy”. At the end of a process of abstract analysis, 47 papers were selected [19–66].

Results

Besides arthralgias and arthritis, we considered other autoimmune clinical conditions usually associated with articular manifestations such as uveitis, keratoconjunctivitis sicca with oral dryness and painful salivary gland enlargement (Sjogren’s syndrome), dactilitis and bursitis, Reiter’s syndrome. In 90% of the cases, the onset of arthritis is within two weeks after the last instillation, whereas arthralgias can appear in a few days after the beginning of local therapy and usually further instillations aggravate the articular symptoms.

The results of our search is listed in Table 1 and the percentage of the different autoimmune manifestations is shown in Fig. 1

Table 1. Revision of the cases reported in world literature
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Fig. 1
figure 1

Percentage of different autoimmune manifestations after BCG immunotherapy. 1 Reiter’s syndrome; 2 Sjogren’s syndrome; 3 arthritis + fever; 4 arthralgias ± arthritis; 5 peripheral arthritis in ankylosing spondylitis; 6 psoriatic arthropathy

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Fig. 2
figure 2

Possible scenario explaining local (a) and articular (b) immunological response to intravesical BCG immunotherapy

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All the papers described at least one case of articular manifestations after BCG immunotherapy for bladder cancer. The response to treatment was variable: some patients experienced clinical remission using NSAIDs alone following BCG discontinuation, while others needed corticosteroids or immunosuppressive treatment. None of the clinical characteristics analyzed in the patients were predictive of systemic side effects after intravesical immunotherapy [67] and the development of a chronic process has been found to be associated with the genetic background [63].

Discussion

The BCG immunotherapy used in bladder cancer does not exert a direct effect on tumor cells. Clinical and laboratory evidences suggest that the antitumor activity is concentrated at the site of BCG instillation and this strengthens the view that local immune mechanisms are responsible for the therapeutic effect of BCG. Indeed, BCG instillation induces an early granulocytic influx into the bladder wall, followed by mononuclear cells, predominantly CD4+ T cells [68]. The predominance of CD4+ T cells is confirmed by the demonstration of a proinflammatory Th1-type cytokine response after BCG stimulation [69]. Similar data are confirmed by Luo et. al, who analyzed the cytokines secreted after BCG stimulation and found an increase of INFγ indicative of a Th1 response to bladder immunotherapy. These authors underlined the pivotal role played by Th1 lymphocytes for successful treatment of superficial bladder carcinoma and reported, both in mice and in human cell cultures, the increase of INFγ after BCG stimulation [70]. Moreover, the addition of exogenous cytokines such as IL2, IL12, IL18 to cell cultures dramatically increases the production of INFγ [71, 72]. Saint et al. [73] have described a different urinary cytokine profile in responding and no-responding patients after BCG-therapy, showing that a Th1-type response is often associated with a favorable response.

To overcome the resistance to local immunotherapy, some authors have proposed the combined use of intravesical BCG plus INF-γ2B to improve clinical efficacy also in those patients nonresponsive to previous intravesical BCG therapy [67].

Recently, a recombinant BCG strain secreting murine IFNγ (rBCG–IFNγ) was generated and tested for its immunostimulatory ability in several in vitro and in vivo systems. This rBCG–INFγ shows enhanced immunostimulatory potential and may offer new opportunities in the treatment of bladder cancer [74]. To improve the antitumor effect of BCG, recombinant BCG DNA (multi-rBCG) and murine IL-12 DNA (mIL-12) vaccines have been evaluated in xenografted MBT-2 murine bladder tumors. Treatment with multi-rBCG alone induced a significant inhibition of tumor growth; the antitumor effect was increased by the simultaneous use of multi-rBCG and mIL-12, and was correlated with the presence of a Th1 lymphocyte infiltrate and a natural killer cell-mediated cytotoxic immune response [75].

Besides the local effects, the importance of a systemic immune response is underlined by the finding of a restricted usage of the variable region of the T cell receptor β chain expressed by CD8+ cells, both in the periphery and in the synovial fluid of a HLA-B27 positive patient with reactive arthritis [62]. This may indicate a specific stimulation of CD8+ cells by BCG; however, also CD4+ T cells showed a strong in vitro response to mycobacterial antigens. The percentage of the expanded CD8+ T cells decreased after remission of the symptoms. The authors concluded that in their patient a cytotoxic immune response triggered by BCG instillation may be enhanced by cross-reactivity with the patient’s self heat shock protein (HSP) presented by the HLA-B27 molecule.

Indeed infections, both viral and bacterial, are known to be able to trigger an autoimmune response and ultimately an autoimmune disorder through a mechanism of molecular mimicry [76]. The mechanism of action of BCG-induced arthritis is unclear; however, a molecular mimicry mechanism has been suggested by studies on adjuvant arthritis [58, 77–79].

In 1986, Shoenfeld et al. [80] described the presence of cross-recognition of mycobacterium and host-derived antigens: monoclonal anti-DNA antibodies obtained from patients with SLE and from mice with a SLE-like disease, were found to bind to glycolipids derived from mycobacterial wall; the binding was inhibited by prior incubation of antibodies with anti-ssDNA or glycolipid antigens. Autoantibodies have been found with high frequency in the blood of patients infected with chronic pulmonary tuberculosis [81], indicating that mycobacteria share antigens with human tissues leading to the production of autoantibodies during mycobacterial infections. Indeed, in a mouse model, monoclonal anti-Mycobacterium tuberculosis antibodies recognize autoantigens such as thyroglobulin, myosin, actin and collagen [82] and autoantibodies from rats with experimental autoimmune enchefalomyelitis recognize mycobacteria antigens [83].

At cellular level, an arthritogenic T lymphocyte clone recognized antigens derived from Mycobacterium tuberculosis and from cartilage proteoglycans [84].

These observations, both at humoral and cellular levels, suggest once again that a molecular mimicry mechanism may be responsible for the joint aggression after the local bladder BCG immunotherapy (Fig. 2).

Following intravesical BCG immunotherapy, urothelial cells express HLA-DR class II antigens which persist for several months after immunotherapy [85]. Considering that CD4+ T cells are powerfully stimulated by mycobacterial infection, it is possible that CD4+ T cells specific for an antigen shared by cartilage and mycobacterium are activated by antigen presenting cells mounting the shared peptide on a class II molecule. Therefore, this T cells specific for a mycobacterium-derived peptide may cross-react with the cartilage-derived peptide, leading to joint aggression and damage by a molecular mimicry mechanism. The mechanism of cross-reaction may also involve a member of the HSP family [62]. HSPs are essential for cellular homeostasis under normal conditions and they also function as molecular chaperones to fold and transport proteins. HSPs are major antigenic determinants and important immunoregulatory agents induced by various types of stress to protect cells from environmental damage [86]. A strong sequence homology between mycobacterial and human HSPs has been demonstrated [87], and cross-reactivity between mycobacterial and human HSP60 seems to be necessary to induce autoimmunity [88]. Hara et al. [89] have shown that transfection of mouse melonama cell line (B16) with the gene encoding for HSP65 of Mycobacterium tuberculosis (B16/65 kDa) enhances the antitumour effect of BCG therapy. Such antitumour effect against B16/65 kDa was abolished by depletion of CD4+ T cells, confirming the pivotal role played by CD4+ T cells in the killing mechanism associated with BCG immunotherapy. It is therefore possible that the immune response initiated by BCG instillation may rely on the cross-reactivity between self and BCG-derived HSP and that HLA molecule may play a role in the presentation of the HSP-antigen.

Indeed, the autoimmune response after BCG therapy seems to occur particularly in genetically susceptible individuals, such as those with HLA-B27 (about 60% of the patients are HLA-B27 positive) [63] or HLA-B7, that shows strong affinity to HLA-B27.

The majority of patients who developed arthralgias and arthritis after BCG immunotherapy usually experienced a good recovery; this is probably related to the discontinuation of the immunotherapy itself. Only a small percentage of subjects present a chronic process and consequently need a long-term therapy.

The treatment varies from NSAIDs alone, NSAIDs plus corticosteroid, corticosteroid alone or plus isoniazid or rifampicin (Table 1). Hydroxichloroquine is also used together with prednisone or with NSAIDs, when the association of prednisone–NSAIDs is not efficacious. In case these treatments do not have beneficial effects and symptoms persist for months or years, immunosuppressive therapies, such as methotrexate or cyclophosfamide are needed. It has been suggested that all patients should receive a course of isoniazid in addition to the described therapy, in case of poor response or severe symptoms [19], but this is still controversial. Indeed, the use of isoniazid seems to be useful to prevent the development of arthritis, but animal models have shown a reduction of the antitumor effect following such profilaxis [90].

In conclusion, reactive arthritis following BCG immunotherapy is a rare event; however, it has to be carefully evaluated since the immediate suspension of BCG intravesical instillation may prevent a chronic arthritis and the need for an immunosuppressive treatment.