Reply to the letter to the editor ‘Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer’ by Yang et al.
Authors: Vincenza Conteduca, Ugo De Giorgi, Gianfranco Lauletta
Journal: Annals of Oncology (2018)

We read with great interest the article by Yang et al. [1.Yang D.D. Krasnova A. Nead K.T. et al.Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer.Ann Oncol. 2018; 29: 386-391Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] first reporting the association between androgen deprivation therapy (ADT), especially for long-term treatment, and the development of rheumatoid arthritis (RA). Interestingly, considering that autoimmunity is more frequent in female sex, this study addressed the possible immunosuppressive action of testosterone, likely responsible of ADT-related autoimmune diseases due to thymic regeneration with an increase of T cells [2.Smolen J.S. Aletaha D. Barton A. et al.Rheumatoid arthritis.Nat Rev Dis Primers. 2018; 4: 18001.Crossref PubMed Scopus (623) Google Scholar]. RA is a chronic autoimmune-inflammatory disease that primarily affects the joints. It is characterized by a complex etiopathogenesis involving autoantibodies against modified self-proteins, stromal and immune cells, circulating pro-inflammatory cytokines/chemokines, and multiple genetic and no-genetic risk factors. Among mechanisms that might contribute to RA development, abnormalities in TP53 and PTEN genes have been demonstrated. Particularly, downregulated PTEN expression, cooperating with TP53, is a characteristic of activated synovial fibroblast of RA patients displaying a significant role in inflammation and immune response by modulating various cytokines production and T-cell lineage [2.Smolen J.S. Aletaha D. Barton A. et al.Rheumatoid arthritis.Nat Rev Dis Primers. 2018; 4: 18001.Crossref PubMed Scopus (623) Google Scholar]. This aspect of RA pathogenesis makes the article even more interesting because the association of long-term ADT and risk of RA could be due to not only to immunosuppressive action of testosterone, as the authors discussed, but also to PTEN alterations, an early frequent event in prostate carcinogenesis. Genomic studies on tumor tissue from patients developing RA in this work are warranted to better understand RA pathogenesis and potential prognostic-therapeutic implications. Beyond genomic alterations, the autoimmune-inflammatory response in RA may require, in most cases, a second hit leading to immune-complex formation and complement activation, to induce or increase cytokine production and synovial vascular leakage. Similar events have been extensively described in several chronic inflammatory disorders due to different etiologies. For example, HCV chronic infection sustains B cells clonal expansion and autoantibodies production (i.e. IgM molecules with rheumatoid factor activity), characterizing mixed cryoglobulinemia, a model of autoimmunity, involving immune complexes formation, cytokines and complement activation [3.Lauletta G. Russi S. Conteduca V. et al.Hepatitis C virus infection and mixed cryoglobulinemia.Clin Dev Immunol. 2012; 2012: 502156.Crossref PubMed Scopus (47) Google Scholar]. Consequently, the knowledge of baseline features as potential triggers of autoimmunity, would have been useful to better characterize the onset and activity of RA, likely also correlated with progression of damage and disability. Lastly, current findings established a significant relationship among chronic inflammation, metabolic syndrome and prostate cancer [4.Conteduca V. Caffo O. Derosa L. et al.Metabolic syndrome in castration-resistant prostate cancer patients treated with abiraterone.Prostate. 2015; 75: 1329-1338Crossref PubMed Scopus (17) Google Scholar, 5.Conteduca V. Caffo O. Galli L. et al.Association among metabolic syndrome, inflammation, and survival in prostate cancer.Urol Oncol. 2018; 36: 24Crossref Scopus (15) Google Scholar]. Yang et al. [1.Yang D.D. Krasnova A. Nead K.T. et al.Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer.Ann Oncol. 2018; 29: 386-391Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] could evaluate the impact of RA development on clinical outcome and probably the detection of autoimmune disease during cancer history might provide a proper management of prostate cancer patients in both early and late disease stages. Recently, our group showed that pre-treatment metabolic syndrome/inflammation status had a negative impact on progression-free/overall survival (PFS/OS) [5.Conteduca V. Caffo O. Galli L. et al.Association among metabolic syndrome, inflammation, and survival in prostate cancer.Urol Oncol. 2018; 36: 24Crossref Scopus (15) Google Scholar]. A subanalysis showed that 23 of 551 (4.2%) castration-resistant prostate cancer patients treated with abiraterone or enzalutamide had an autoimmune condition, of whom 8 (1.5%) was affected by RA. Pre-therapy metabolic/inflammatory alterations were observed in 17 out of these 23 (73.9%) patients (P = 0.045) who had a shorter PFS/OS [hazard ratio (HR) = 3.7, 95% confidence interval (CI) 2.9–5.9, P < 0.0001 and HR = 5.8, 95% CI 4.0–14.3, P < 0.0001, respectively). These evidences confirm the importance of identifying autoimmune disease during ADT not only in localized disease but also in all steps of prostate cancer, especially for the growing number and increasingly early use of new hormonal prolonging-life drugs. None declared.