Long-Term Safety and Curvature Deformity Characterization in Patients Previously Treated with Collagenase clostridium Histolyticum for Peyronie's Disease.

PURPOSE: We assessed the long-term safety and immunogenicity profile of collagenase clostridium histolyticum and characterized penile curvature deformity over time in patients previously treated for Peyronie's disease. MATERIALS AND METHODS: This phase 4 study included men who received collagenase clostridium histolyticum in either 12-month, double-blind, placebo controlled clinical trials (IMPRESS I/II), or one of two 9-month open label studies. Eligible patients received no additional collagenase clostridium histolyticum treatment and were followed once yearly for up to 5 years to assess Peyronie's disease clinical symptoms, patient reported outcomes and safety. RESULTS: Of 280 patients enrolled 204 (73%) completed the study. At baseline 247 patients had already experienced a mean±SD penile curvature decrease from 51.8±15.0 to 31.0±16.1 degrees (improvement of 20.9±16.2 degrees or 39.5%). At year 5 in 180 patients, despite no additional treatment, there was an additional 9.1% improvement in mean penile curvature compared with reference data (4.3±13.4 degrees, 95% CI 2.3-6.2, p <0.02). At baseline 183 patients experienced mean Peyronie's Disease Questionnaire bother domain score improvement from 6.5±3.5 to 3.4±3.3. At year 5 there was additional score improvement to 2.4±2.9 (p=0.0003). Adverse events were reported in 17.5% (49) of patients but no adverse events were considered treatment related. No long-term safety issues were identified up to 5 years after treatment. Long-term immunogenicity profiling showed a decreasing trend in the number of anti-AUX-I and anti-AUX-II seropositive cases at years 4 and 5 after collagenase clostridium histolyticum treatment. CONCLUSIONS: Most patients treated with collagenase clostridium histolyticum continued to have penile curvature and Peyronie's Disease Questionnaire domain score improvements through year 5 without additional collagenase clostridium histolyticum treatment, and no additional safety signals were identified.

The role of inflammatory parameters (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-eosinophil ratio) in patients with Peyronie's disease.

OBJECTIVES: The aim of the study was to investigate the ability of the systemic inflammatory parameters to predict the discrimination of the phases of Peyronie's disease (PD). MATERIALS AND METHODS: Demographic, clinical, and laboratory data from 156 patients with PD were analyzed. A complete blood count (CBC) was obtained for every patient, and the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-eosinophil ratio (MER) were calculated for every men. Subsequently, patients were divided into two groups based upon the phase of the disease. RESULTS: The mean age was 51.9 ± 9.6 in all study population. The mean duration between symptom onset and patient evaluation was 4.2 ± 3.2 months in acute phase group, while it was 32.7 ± 31.7 months in chronic phase group (p < 0.001). There were no significant differences between the groups according to comorbidities such as diabetes, hypertension, lipid abnormalities, ischemic heart disease, smoking, and alcohol consumption. There was a statistically significant difference in NLR and PLR between two groups (p = 0.008, p = 0.008, respectively). NLR and PLR were significantly correlated with discrimination status in univariate analysis (p = 0.003, p = 0.005, respectively). Multivariate regression analysis revealed that NLR was the only independent risk factor for discrimination of the phases of PD (p < 0.001). The ROC analysis revealed a cutoff value of 1.8 (AUC 0.712, p < 0.001; sensitivity 61.1%; specificity 75.0%) for the NLR. CONCLUSION: Our study demonstrated that NLR could be helpful to differentiate the chronic phase from the acute phase in patients with PD. Therefore, NLR could be used as an objective biomarker to the management of the disease and choosing the appropriate treatment.

Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease.

INTRODUCTION: Peyronie's disease (PD) is a debilitating affliction for the male population, causing severe curvatures to the erect penis and erectile dysfunction in about 50% of men. This deviation of the penis significantly impairs sexual intercourse and causes depression and strains in the relationship. As of today, medical treatment options are few and far between, with surgery remaining as the sole reliable treatment. AIM: To give a general overview regarding fibrosis and the specific role of extracellular matrix, macrophages, and myofibroblasts in PD. Additionally, we will provide an overview of past and present research and how this has shaped our vision concerning the pathophysiology of PD. METHODS: We performed a non-systematic literature review using the search terms "fibrosis," "pathophysiology," "myofibroblast," "extracellular matrix," "Peyronie's disease," and "drug discovery." MAIN OUTCOME MEASURE: We assessed current knowledge regarding fibrosis in PD and the possibility to use this knowledge for new treatment options. RESULTS: Interpreting findings from the most recent next-generation sequencing, in vitro and in vivo PD research, we provide novel insights for the pathophysiology of PD. Using this knowledge, we will attempt to provide future directions for PD research and drug discovery, which is urgently needed, because its treatment has essentially been stagnating for about 30 years. CONCLUSION: Historically, PD has not been studied as widely as kidney, lung, or hepatic fibrosis, and our knowledge of its pathophysiology still remains relatively obscure. Nonetheless, recent breakthroughs using stem cells, next-generation sequencing, and phenotypical screening assays bring us several steps closer to filling the gaps in our knowledge. In the near future, clinical trials will prove essential to translate this plethora of preclinical data into usable tools that can improve the lives of many of our patients. Milenkovic U, Ilg MM, Cellek S, et al. Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease. Sex Med Rev 2019;7:679-689.

Peironimev-Plus® in the treatment of chronic inflammation of tunica albuginea (Peyronie's disease). results of a controlled study.

Peyronie's Disease (PD) is a connective tissue disorder involving the growth of fibrous plaques in penile corpora cavernosa (tunica albuginea). The conservative treatment is indicated in the development stage of PD for at least one year after diagnosis and in case of penile pain. This study was conducted to demonstrate the possible effectiveness of the new substances of Peironimev-plus®. Sixty four patients (age: 29-65 years, mean: 52.57 ± 9.06) diagnosed with PD were enrolled in a medical treatment. All patients underwent the following diagnostic tests: penile ultrasound, photographic documentation of penile curvature, IIEF questionnaire (erectile function score), pain evaluation with Visual Analogue pain Scale (VAS). The patients were divided into two treatment groups with different combinations of drugs: A = Peironimev-plus/oral/one tablet-daily + Verapamil injection (peri-lesional) 10 mg/every two weeks + Verapamil iontophoresis/5 mg/three times a week - for 6 months; B = Verapamil injection (peri-lesional) 10 mg/every two weeks + Verapamil iontophoresis/5 mg/three times a week - for 6 months. Intergroup analysis revealed statistically significant differences: in group A the effective plaque size reduction was -30.8% while in the group B the reduction was -18.0% (p=0.000). In group A the improvement of curvature occurred in 85.1% of the cases while in group B this occurred only in 53.5% (p=0.024), moreover the mean curvature decrease was respectively - 8.7° and - 4.6° (p=0.002). IIEF score was significantly improved in group A patients with erectile dysfunction (p=0.02). Our results suggest that Peironimev-plus is an effective drug in treating PD and it may help to prevent the progression of PD.

Significant alterations of serum cytokine levels in patients with Peyronie's disease.

OBJECTIVE: To determine the expression of the cytokines transforming growth factor-beta1 (TGF-beta1), interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in serum from patients with Peyronie's disease (PD) compared to healthy controls. MATERIALS AND METHODS: Ninety-one consecutive PD patients aged 20 - 74 years were included in this study. All patients were diagnosed with symptomatic PD for the first time and had a palpable penile plaque. The patients previously had the disease for 6 - 72 months. None of the patients had a severe infectious disease or known systemic illness. For cytokine analyses, peripheral venous blood samples were obtained before treatment. Fifty healthy male blood donors aged 22 - 64 years served as the control group. TGF-beta1, IFN-gamma, Il-6, and TNF-alpha were analyzed quantitatively with commercial immunoassays. RESULTS: Mean cytokine levels in serum from patients were increased for TGF-beta1 and IFN-gamma compared to healthy controls. The difference for TGF-beta1 was considered statistically significant (p < 0.001). IL-6 was not detectable in PD patients (p < 0.01) and TNF-alpha was decreased (p < 0.0001). CONCLUSION: The significantly elevated serum level of the profibrotic TGF-beta1 cytokine underscores the effect of cytokines in the pathophysiology of PD. The significantly decreased TNF-alpha serum level suggested no acute immunomodulatory process. Therefore, the relevance for therapeutic administration of TNF-alpha should be further investigated. Quantification of TGF-beta1 in serum of PD patients provides a possible diagnostic tool and target for therapy. The data on altered cytokine levels in PD patients also provide a new understanding for etiopathogenesis of PD, which warrants further investigation.

Significant alterations of serum cytokine levels in patients with Peyronie's disease

OBJECTIVE: To determine the expression of the cytokines transforming growth factor-beta1 (TGF-beta1), interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in serum from patients with Peyronie's disease (PD) compared to healthy controls. MATERIALS AND METHODS: Ninety-one consecutive PD patients aged 20 - 74 years were included in this study. All patients were diagnosed with symptomatic PD for the first time and had a palpable penile plaque. The patients previously had the disease for 6 - 72 months. None of the patients had a severe infectious disease or known systemic illness. For cytokine analyses, peripheral venous blood samples were obtained before treatment. Fifty healthy male blood donors aged 22 - 64 years served as the control group. TGF-beta1, IFN-gamma, Il-6, and TNF-alpha were analyzed quantitatively with commercial immunoassays. RESULTS: Mean cytokine levels in serum from patients were increased for TGF-beta1 and IFN-gamma compared to healthy controls. The difference for TGF-beta1 was considered statistically significant (p < 0.001). IL-6 was not detectable in PD patients (p < 0.01) and TNF-alpha was decreased (p < 0.0001). CONCLUSION: The significantly elevated serum level of the profibrotic TGF-beta1 cytokine underscores the effect of cytokines in the pathophysiology of PD. The significantly decreased TNF-alpha serum level suggested no acute immunomodulatory process. Therefore, the relevance for therapeutic administration of TNF-alpha should be further investigated. Quantification of TGF-beta1 in serum of PD patients provides a possible diagnostic tool and target for therapy. The data on altered cytokine levels in PD patients also provide a new understanding for etiopathogenesis of PD, which warrants further investigation.

[Conservative treatment of Peyronie's disease in the light of new pathogenetic data].

The study of pathogenetic mechanisms of Peyronie's disease (PD) in respect of raising efficacy of complex conservative therapy was made in 41 patients with PD. The control group consisted of 266 persons. Immunological and virusological investigations were made using enzyme immunoassay. HLA typing of class I antigens was made, antinuclear antibodies and antibodies to DNA were investigated. Effects of intron A and verapamil on proliferation of penile tunica albuginea were studied in vitro. Conservative therapy was given to 32 patients with acute PD. Patients with PD were found to carry chronic infection with type II herpes significantly more frequently. There was a significant association of PD with HLA-antigen B8 with high percentage of diagnostic titers of antinuclear antibodies. In vitro effect of intron A and verapamil was found to be dose- and time-dependent. Verapamil has a narrow range of dose-dependence and cytotoxicity in high concentrations. Combined treatment raised the proportion of good results while that of satisfactory outcomes decreased. Viral infection may be involved in pathogenesis of PD. This infection may alter mechanisms of immune regulation and start of autoimmune process in predisposed patients. Combination of magnetolaser therapy with intron A injections is an effective method of acute PD treatment. The addition of specific antiviral therapy raises treatment efficacy by action on one of pathogenetic mechanisms of the disease.

Peyronie's disease in men with HIV responding to highly active antiretroviral therapy.

The pathogenesis of Peyronie's disease (induratio penis plastica) is unclear, but immune phenomena appear likely to be involved. Two cases are presented where the condition developed in temporal association with a virological response to highly active antiretroviral therapy (HAART) in men with HIV infection. It is suggested that this may represent another manifestation of immune restoration disease.

Prospective analysis of HLA classes I and II antigen frequency in patients with Peyronie's disease.

PURPOSE: The pathogenesis of Peyronie's disease remains unclear. Previous studies have described possible associations among various HLAs and Peyronie's disease. However, only small series comprising 9 to 52 patients were analyzed in these studies and published results are controversial. We prospectively investigated a possible association of Peyronie's disease with HLA classes I and II specificity in a large patient group. MATERIALS AND METHODS: A total of 154 consecutive patients with Peyronie's disease were typed serologically for HLA class I antigens. Molecular typing of HLA class II alleles was performed by polymerase chain reaction sequence specific primers. Results were compared with those in healthy bone marrow donors for HLA classes I (2,450) and II (316), serving as representative controls selected from the local population. In addition, HLA distribution in a German normal cohort of 14,835 individuals served as a control. RESULTS: No significant difference in HLA classes I and II antigen frequency was evident in patients with Peyronie's disease compared with healthy controls. CONCLUSIONS: The results of this study do not indicate any significant association between Peyronie's disease and antigens of the HLA system.

The genetics and immunology of Peyronie's disease.

Peyronie's disease (PD) is a condition characterized by localized and often progressive fibrosis and scarring of the penis. This condition has an unknown etiology although several hypotheses have been proposed. These include traumatic, immunologic and genetic causes. We studied the genetics and immunology of PD using both molecular biologic and molecular genetic techniques. Men (n=283) with PD were identified by retrospective chart review of one physician's office practice. These men were contacted by telephone and asked to submit to an interview and blood test for genetic studies. Simultaneously, tissue and cells collected in the laboratory were examined by Western and Northern blot analysis for examination of protein and RNA for expression of HLA. Of the first 107 men contacted, 24 were available and consented to interview and blood testing. The mean age was 60.3 y with an average duration of PD of 4.9 y. One patient had a family history of PD while no patients had Dupuytren's contracture. Twenty patients were considered to have primary disease while four were secondary. Eleven patients had tissue prepared for Northern blot analysis and nine patients were the subject of Western blot analysis. All tissue, both Peyronie's and control expressed class I MHC while no tissue expressed class II MHC. The expression of mRNA of class I MHC was equal for Peyronie's and control patients while the expression at the protein level was less in the PD patients. We conclude that PD may have multiple etiologic agents. One cannot exclude a class II MHC association but in our population, HLA DQ is not expressed. Class I MHC may be involved as the expression of class I MHC protein is different in Peyronie's patients than in controls. Genetic studies are ongoing. International Journal of Impotence Research (2000) 12, Suppl 4, S127-S132.

Immunologic findings in Peyronie's disease: a controlled study.

OBJECTIVES: Recent literature suggests the hypothesis of an immune etiology of Peyronie's disease. In this controlled study, the immune response pattern of the disease is investigated. METHODS: Sixty-six patients with Peyronie's disease and 20 age-matched controls were studied. In all patients, skin test (multitest), in vitro lymphocyte transformation test (LTT), serum immunoglobulin (Ig) A, G, and M, anti-DNA, antinuclear and anti-smooth muscle cell antibodies, C3 and C4 complement fractions, antistreptolysin, and C-reactive protein titers were evaluated. RESULTS: A fair percentage (75.8%) of the patients with Peyronie's disease exhibited at least one abnormal immunologic test, in comparison to only 10% among controls (chi-square = 27.8, df = 1; P < 0.0001). Alterations of cell-mediated immunity (multitest, LTT) were observed in 48.5% of patients, alterations of humoral immunity (Ig) in 31.8%, and alterations of markers of autoimmune disorders (autoantibodies, complement activation) in 37.9% of the cases. CONCLUSIONS: Our results support the hypothesis that there is some involvement of the immune system in the pathogenesis of Peyronie's disease, although the available data still appear to be insufficient to formulate a definite pathogenetic hypothesis.

Is there an immunogenetic basis for Peyronie's disease?

PURPOSE: Despite numerous studies, there has been no definitive HLA association with Peyronie's disease. Results of available studies have been reviewed and compared to determine if the cumulative evidence supports any immunogenetic, HLA association with Peyronie's disease. MATERIALS AND METHODS: Data from reports of HLA associations with Peyronie's disease were reanalyzed by categories of reported HLA class I or class II antigens in comparison with recently available large population analysis of the frequencies of these antigens in the normal population. Data were also considered by whether they were derived from population or family analyses. RESULTS: The results of 4 series of patients testing an association of Peyronie's disease with the HLA class I antigens, in particular the B7 related antigens, were contradictory. A B7 association was not confirmed in 2 larger series and, in fact, the B7 related antigens were observed in frequencies expected in a normal population, suggesting that the associations observed in the smaller series were due to chance. An association with the HLA class II antigen, DQ2, was found in 1 of the larger series. Reported family studies suggest a genetic basis for Peyronie's disease but do not indicate a gene closely linked to the HLA complex. CONCLUSIONS: Considering all available data, Peyronie's disease appears to be multifactorial in pathogenesis. Because Peyronie's disease is likely heterogeneous and because available studies have analyzed serologically defined HLA antigens, future studies to define HLA alleles molecularly and to characterize patient subgroups may clarify an immunogenetic basis.

Peyronie's disease is associated with an HLA class II antigen, HLA-DQ5, implying an autoimmune etiology.

PURPOSE: Previous studies using serological (protein based) HLA typing methods suggested an association between various HLA antigens and Peyronie's disease. We used a molecular (deoxyribonucleic acid based) HLA typing method to determine whether Peyronie's disease is associated with class II HLA antigens. MATERIALS AND METHODS: Class II HLA typing using the polymerase chain reaction-sequence specific primer method was performed in 31 patients with Peyronie's disease, 19 age matched urological patients with disorders other than Peyronie's disease and 75 major organ donor cadavers representative of the general population. RESULTS: The frequency of HLA-DQ5 was significantly increased in patients with Peyronie's disease (61% HLA-DQ5 positive) compared to age matched disease-free controls (11% HLA-DQ5 positive, corrected p = 0.003) and general population controls (25% HLA-DQ5 positive, corrected p = 0.005). The relative risk for Peyronie's disease associated with HLA-DQ5 was 12.7 and 4.6 compared to age matched and general population controls, respectively. CONCLUSIONS: This study shows a positive association for the HLA class II antigen HLA-DQ5 with Peyronie's disease, suggesting that HLA-DQ5 is a risk factor for Peyronie's disease and implying an autoimmune etiology for this disorder.

The immunological features of Peyronie's disease.

PURPOSE: We investigated the immunological features and possible autoimmune basis of Peyronie's disease. MATERIALS AND METHODS: The sera of 100 patients with Peyronie's disease were tested for circulating autoantibodies, including anti-penis antibodies, by indirect immunofluorescence. Antibody deposition and the immunological activity in Peyronie's plaque tissue from patients with early and long-standing disease were also assessed. RESULTS: Circulating anti-penis antibodies were not found in any patient although antinuclear antibodies were present in 24%. Patients with early Peyronie's disease had IgM antibody deposition, marked T lymphocytic and macrocytic infiltration in the sub-tunical space, increased expression of adhesion molecules by endothelial cells and an increased human lymphocyte antigen class 2 expression by the cellular infiltrate, indicating cellular immune activation. CONCLUSIONS: These results show that some of the features of autoimmunity, in particular the cell mediated response, are present in Peyronie's disease.

Increased serum levels of anti-elastin antibodies in patients with Peyronie's disease.

The cause of Peyronie's disease is unknown. Immunological mechanisms in the pathogenesis have been previously suggested. Antibodies to elastin are present in all individuals. However, abnormal serum levels of anti-tropoelastin (reflecting elastin synthesis) and anti-alpha-elastin (reflecting elastin destruction) are seen in a variety of autoimmune diseases. We show that patients with Peyronie's disease have higher levels of antibodies to tropoelastin (p < 0.047) and alpha-elastin (p < 0.012) than age-matched controls, suggesting an increase in elastin synthesis and breakdown, respectively. These findings suggest the presence of autoimmune mechanisms in the pathogenesis of Peyronie's disease, which may have future diagnostic and therapeutic implications.

HLA antigens in Peyronie's disease.

This study presents data on HLA phenotypes of 52 unrelated patients suffering from idiopathic Peyronie's disease. This first investigation on HLA class II antigens detected an association of HLA-DR3 and -DQw2 in this disorder. HLA typing was done from ACD-stabilized peripheral blood using the modified lymphocytotoxicity test. Antigen frequencies of the patient group were compared with those of healthy individuals of the local population. There were no deviations of frequencies for antigens of the B7 cross-reacting group as described in earlier studies. In addition none of the other class I antigens (HLA-A, -B, -C) showed any significant deviation in frequencies after correction of p values. Regarding class II antigens HLA-DR3 was detected in the patient group in 33.3% compared with 16.0% of the control population (corrected p < 0.05). The closely linked antigen DQw2 was found in 58.8 compared with 31.2% (corrected p < 0.005). Not only genetic factors can be stated by these findings. As HLA-DR3 and -DQw2 are known to be the typical associated antigens of organospecific autoimmune disorders, this suggests possible autoimmunological factors in this disorder of otherwise unknown etiology.

HLA association of idiopathic Peyronie's disease: an indication of autoimmune phenomena in etiopathogenesis?

HLA typing for class I and class II antigens was done in 52 unrelated patients suffering from idiopathic Peyronie's disease. The controversially discussed association with the HLA-B7 cross-reacting group could not be confirmed. Marked deviations of antigen frequencies were observed for HLA-A1, B8, Cw7, DR3 and DQw2 compared to healthy local controls. After correction of p-values, A1 (pc less than 0.05) and DQw2 (pc less than 0.01) remained significant. A possible association of Peyronie's disease with markers of the HLA-A1, B8, Cw7, DR3, DQw2 haplotype, as first described here, would suggest autoimmunological factors in this disorder of otherwise unknown etiopathogenesis.

Humoral immune responses in Peyronie's disease patients receiving clostridial collagenase therapy.

Human IgG and IgE antibody responses to clostridial collagenase (Nucleolysin) were monitored in 150 untreated healthy blood donors and 44 patients receiving intrapenile injections of collagenase for treatment of Peyronie's disease. Pre, 1 and/or 2 month post treatment sera were analyzed in radioimmunoassays for human IgG and IgE antibodies using solid phase purified Cl. histolyticum collagenase to extract antibodies from serum and 125I-Protein A or rabbit anti-human IgE to detect bound IgG and IgE, respectively. IgG and IgE antibody levels greater than 2.5 Units and 0.2 per cent Bmax, respectively, were considered positive if the binding was greater than 80 per cent inhibitable with soluble collagenase. IgG anti-collagenase was detected in 34 per cent of the 150 healthy controls and 58 per cent (24/41) of untreated Peyronie's disease patients. Intralesional injection of 3,000 to 12,650 Units of collagenase induced an increase of two- to 10-fold in the IgG levels at one to two months in 88 per cent of patients. Of the 186 individuals tested, only one (0.5 per cent) had detectable collagenase-specific IgE antibody in his serum as defined by positive threshold and antigen inhibition criteria.

HLA-A and B antigens in patients with Peyronie disease.

Using microdroplet lymphocyte cytotoxicity test, as a method of HLA typing, 9 patients with Peyronie disease were studied from a viewpoint of relationship between this disease and HLA-A and B antigens. The frequencies of each antigen in the patients were compared with those of healthy controls. No significant difference of distribution in HLA antigens was observed between the patients and the control group.