Comment to “Acute Arthritis Secondary to Intravesical Bacillus Calmette-Guérin for Bladder Cancer”

Martínez-Piñeiro, J.A.

doi:10.1016/j.acuroe.2012.03.003

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Martínez-Piñeiro" "autores" => array:1 [ 0 => array:3 [ "nombre" => "J.A." "apellidos" => "Martínez-Piñeiro" "email" => array:1 [ 0 => "mpineiro@telefonica.net" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Club Urológico Español de Tratamiento Oncológico (CUETO)" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comentario Editorial a “Artritis Aguda Secundaria a Bacilo de Calmette-Guérin Intravesical en el Cáncer de Vejiga”" ] ] "textoCompleto" => "Drs. Raheem, Kalunian, and Parsons, belonging to the divisions of Urology, Rheumatology and Urologic Cancer of the University of California, San Diego, published a review article on the little-known side effect of intravesical administration of bacillus Calmette-Guérin (BCG), arthralgia, or reactive arthritis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The scarcity of publications on this topic in the urological literature seems to suggest that it is a poorly characterized toxicity.Although the prevalence of this arthralgia is estimated at 0.5–1% of patients receiving intravesical BCG, the authors found only 4 review articles published in English, plus 23 clinical cases and one patient in the institution, which together are 40 cases. Most articles appear in Rheumatology (45%) and Internal Medicine (33%) journals; only 6 articles were published in urological journals (33%). Considering the thousands of patients who have received BCG instillations worldwide (the CUETO Group alone has recruited 1888 patients for its 5 studies), it is clear that the prevalence of this adverse effect has to be far superior to that published in the literature.The update of the 2011 clinical guidelines of the European Association of Urology for non-muscle-invasive urothelial carcinoma of the bladder (NMIUCB)<a class="elsevierStyleCrossRef" href="#bib0010">2</a> does not even mention this adverse effect, and it merely expresses that with the greater experience we have in the use of the BCG, the side effects appear to be less important, reducing the frequency of the serious adverse effects to 5%. A review of the clinical guidelines and recommendations of the International Bladder Cancer Group (IBCG) on NMIUCB only cites arthralgia, along with skin rash among the allergic type systemic reactions of the BCG, without citing the prevalence, or any other feature, merely recommending antihistamines and non-steroidal anti-inflammatory drugs for grade 1–2 toxicity and considering the treatment with isoniazid, rifampicin, and corticosteroids for grades 3–4, as well as instillation suspension in all cases.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Another comprehensive review by Gontero et al.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> on the role of the BCG in the treatment of NMIUCB, including articles in Pub-Med, Embase, and the Cochrane Central Register of Databases of Controlled Trials, during the period from 1976 to November 2008, does not even mention this adverse effect in a very detailed table that takes up two full pages.Given the rarity and scarce severity that reactive arthritis or arthralgia due to BCG usually has, the CUETO Group did not specify this adverse effect in the data collection forms of their first randomized prospective studies, which was registered within systemic toxicity, so we lacked data on its prevalence. However, it was included in the forms of the 98013 study started in 1999,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> which compares in Ta G3–T1 G3–Cis tumors the efficacy of induction with 6 instillations of 81mg of BCG Connaught versus the same induction followed by maintenance with instillation of 81mg every 3 months for 3 years. 397 patients were recruited between August 1999 and March 2007; 195 in induction group A, and 202 in maintenance group B. The final analysis has not yet been published. The mean follow-up in June 2011 was 62.47 months (2–132) for group A and 62 months (3–134) for group B. Among the side effects, there were 5 cases of arthralgia (1.26%), 2 in group A and 3 in B, all occurring during the induction. One of the episodes followed the fourth instillation and the other four the sixth instillation.Of the 3 patients in group B (induction plus maintenance), one of them, who had a mild arthralgia after the sixth instillation, was able to continue the maintenance guideline without any problems. The other two did not start maintenance due to excessive toxicity. Both patients in group A suffered the adverse effect in the last instillation of the induction cycle and, therefore, the BCG was not contemplated anymore.In the article by Raheem et al., we can also check that reactive arthritis occurred between the second and ninth instillations, reaching the maximum frequency after the fourth (25%), fifth (13%) and sixth (14%) ones. The most affected joints were the knee (41%), ankle (26%), and wrist (19%). Polyarthritis was more common than monoarthritis. In 38% of the cases, conjunctivitis was associated, and urethritis in 8%.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>The article by Resel Folkersma et al., referred by Raheem et al., deals with a case of typical Reiter syndrome: bilateral conjunctivitis, swelling of knee and right wrist with limited mobility, balanitis and white urethral discharge. In none of the 6 cases of the CUETO 98013 study, or in the 40 collected by Raheem, did articular puncture reveal the presence of BCG in the synovial fluid, only inflammatory cellularity.Reiter's syndrome is characterized by a reactive arthritis triggered by infections of genitourinary or digestive origin in genetically predisposed, HLA-B27 positive, or HLA-B7 positive men, but the pathophysiology of arthritis associated with BCG is unclear, as it is well exposed by the authors, especially as the tests for the HLA-B27 antigen were positive for only 62% of the patients examined, and in the paper published by Resel Folkersma,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> which contained 4 clinical cases besides his own, only 2 of the 5 patients were HLA-B27 positive (40%).There appears to be no relation with a particular BCG strain and there are no data on the influence of the dose, as the dosing does not appear in this review. But it seems logical that if toxicity is usually dose-related,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> so it is in the case of reactive arthralgia. In the 5 cases of the CUETO 98013 study and in the one discussed above by Resel Folkersma, the dose used was 81mg of the Connaught strain.In conclusion, I would say that arthralgia or reactive arthritis following BCG is not as rare as it is apparent from the literature, that it is not usually a serious complication, and that in mild cases we could try to continue with the instillations, once the joint condition eases." "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Martínez-Piñeiro JA. Comentario editorial a «Artritis aguda secundaria a bacilo de Calmette-Guérin intravesical en el cáncer de vejiga». Actas Urol Esp. 2012;36:467–8." ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Artritis aguda secundaria a bacilo de Calmette-Guérin intravesical en el cáncer de vejiga" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "O.A. Raheem" 1 => "K. Kalunian" 2 => "J.K. 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Actas Urológicas Españolas is an international journal dedicated to urological diseases and renal transplant. It has been the official publication of the Spanish Urology Association since 1974 and of the American Urology Confederation since 2008. Its articles cover all aspects related to urology. Actas Urológicas Españolas, governed by the peer review system (double blinded), is published online in Spanish and English. Consequently, manuscripts may be sent in Spanish or English and bidirectional free cost translation will be provided. It has high visibility and accessibility and is found in the most important data bases, Medline/Pubmed, Emabase, JCR, Ïndice Médico Español, Índice bibliográfico Español en Ciencias de la Salud (IBECS), Cuiden, Dialnet, Hinari, Scopus, Google Scholar.

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