Reactive arthritis following treatment with intravesical Bacillus Calmette-Guerin for papillary carcinoma of bladder

Discussion

Intravesical BCG therapy is considered an effective mode of immunotherapy for superficial bladder cancer. However, though generally well tolerated, ReA is one of the rare complications of this form of treatment. Among the musculoskeletal side effects of iBCG, reported are ‘arthritis and arthralgia’ (0.5%–8.3%), ‘persistent arthritis’ (1.7%), ‘arthralgia’ (28.1%), ‘arthritis’ (3.6%) and ‘musculoskeletal adverse reactions’(3.2%).2 Incidence of ReA following intravesical BCG therapy is 2% as estimated.3

In a review by Bernini et al,2 onset of arthritis was within 2 weeks in 90% of patients from last instillation.4 Mean number of instillations was 5.8 and time elapsed from last instillation was on average 13.5 days.2 Similar number of instillations (5.38) was recorded in the case series by Taniguchi et al.5 Our patient developed symptoms after 10 days from his last iBCG injection. He received a total of five doses of weekly iBCG injections till then.

However, neither the number nor the time elapsed correlates with the prognosis or severity of disease.6

This form of arthritis mainly conforms to either of two clinical patterns and may be associated with other forms of musculoskeletal symptoms like enthesitis, dactylitis, bursitis or tendinitis. Most common form is asymmetrical (59.6%), polyarthritis, with large joints (less commonly small joints) and upper/lower extremity predominance (most commonly knees and ankle followed by wrists).2 5 Although less common, an asymmetric mono-oligoarthritis form which predominantly involves large joints of lower limbs is also seen.7 It usually resolves with discontinuation of iBCG with 70.5% recovering within 2 months2 and 93.2% within 6 months.2 Only ~6% had symptoms more than 6 months.2 Patients with monarthritis had a shorter course (mean duration of 33.5 days) while those with polyarthritis had a longer one (70.1 days).2

In a review by Abdelghani et al, joint pain was the most frequently reported symptom (100%), followed by fever (81%).8 Extra-articular manifestations like urethritis and/or balanitis (35%) cystitis (27%–95%), conjunctivitis (64%) have also been described in a proportion of patients.8

Our patient had asymmetric polyarthritis,with both large as well as small joint involvement and upper and lower extremity involved at same time which is rare. Extra-articular manifestations were not observed. Though BCG-related ReA usually has a favourable outcome, our case had a prolonged course lasting more than 6 months.

The management essentially involves stopping iBCG. Worsening of arthritis has been reported in 83.3% of patients who were continued on iBCG.2 The therapeutic measures are not well established, NSAIDS forming usually the first line of treatment and in resistant cases short-term use of glucocorticoids.2 Most patients recover with NSAID monotherapy (49.4%) with few requiring additional glucocorticoids (10.3% with NSAIDS; 21.8% alone)2 Usual time of resolution is within 6 months, however, for a prolonged disease course, DMARDS may be warranted.2 However, in pan-resistant cases, proposal of isoniazid or rifampicin have been mentioned in the literature but as use of the above drugs can result in loss of efficacy of iBCG, hence their use remains controversial.2 8

In our patient, the arthritis did not respond to the usual line of treatment—discontinuation of iBCG, NSAIDS and glucocorticoids. Treatment with DMARDS was required to prevent further joint inflammation and damage, rarely seen in such cases prevalent in literature.

The main predictors for a chronic course are polyarthritic involvement at onset and/or failure to discontinue BCG.2 In our case, iBCG was promptly discontinued but had polyarticular involvement at the onset as a predictor for chronic course.

The mechanism by which BCG vaccine causes Re A has been explored by various investigators. The common consensus is that it predominantly acts locoregionally by modification of inflammatory response and altered cytokine production.2 However, after repeated weekly doses, due to cross reactivity and molecular mimicry between HLA-B27 (acting as a restriction molecule) and mycobacterial antigen (especially 65 kD HSP) and/or cartilage proteoglycan link protein with occasional antigens spreading from the bladder to the circulation may induce a systemic immune mediated response having the joints as target, particularly in genetically predisposed individuals like those positive for HLA B27 antigen (50.9%).2

Although the overall prevalence of HLA B27 in ReA patients ranges from 50%–80%, the prevalence of HLA in BCG associated Re A has been found out to be much lower (29%).8 It is a known fact that B27 is not a diagnostic tool for acute ReA as it has low predictive value. However, in ReA associated with Salmonella, Campylobacter and Chlamydia, Shigella, etc, it has been regarded as a ‘marker’ of chronicity/severity of arthritis. But in iBCG related ReA, HLAB27 does not correlate with chronicity/severity. Instead it is corroborated with presence of polyarthritis ((47.1%; symmetric (52.9%); asymmetric (47.1%)) than oligoarthritis (39.3%; asymmetric 90.9%; symmetric 9.1%) or monoarthritis (25%).2

A recent two centre study done over two decades by Taniguchi et al 5 showed, in addition to HLA B27, association of HLA-B35, HLA-B39 and HLA-B51 positivity in patients developing ReA post-iBCG therapy for bladder cancer and showed an overall higher prevalence (2%) of this complication in the Asian population.5

Interestingly, Chlamydia serology when done in these patients yielded negative results universally indicating a lack of pathophysiological synchrony with Chlamydia in patients who develop ReA following BCG therapy.8