Conservative treatment of Peyronie's disease: a guide.

PURPOSE: To review the literature on the topic, to suggest a common line of treatment applicable across a wide community of specialists, and to contribute in maintaining the high level of interest in this disease. METHODS: A comprehensive and exhaustive review of the literature was performed, identifying hundreds of articles on the topic. RESULTS: Peyronie's disease is a condition that has been recognized, studied, and treated for centuries; despite this, if one excludes surgery in cases in which the deformity is stable, no clear treatment (or line of treatment) is available for complete relief of signs and symptoms. Treatment options were divided into local, oral, and injection therapy, and a wide variety of drugs, remedies, and options were identified. CONCLUSIONS: Low-intensity extracorporeal shock wave therapy, vacuum therapy, penile traction therapy, phosphodiesterase type 5 inhibitors, hyaluronic acid, and collagenase of Clostridium histolyticum may be recommended only in specific contexts. Further studies on individual options or potential combinations are required.

A 10-Year Review of Collagenase Versus Fasciectomy in the Treatment of Dupuytren Contracture.

BACKGROUND: Dupuytren disease (DD) is one of the most common disorders of the hand, affecting 5.7% to 11.7% of the global population. This study seeks to evaluate the 10-year efficacy of the 2 most prominent treatment modalities for DD in Veterans Affairs hospitals, injectable collagenase Clostridium histolyticum versus open fasciectomy. METHODS: A retrospective review was conducted of all electronic medical records of patients who underwent open fasciectomy or collagenase injection to treat their persistent Dupuytren contracture between April 2011 and April 2021. All procedures were performed by 1 of 5 senior surgeons at the same Veterans Affairs Hospital. RESULTS: A total of 232 patients were treated for DD, with 247 collagenase injections and 44 open fasciectomies performed in this sample. Collagenase patients were, on average, 6.51 years after intervention at the time of review. Open fasciectomy patients were, on average, 4.56 years after operation at the time of review. Collagenase decreased contractures, on average, by 29.40 degrees, whereas open fasciectomy decreased contractures, on average, by 38.59 degrees. Of the contractures that were initially classified as resolved, 50 of 155 (32.2%) treated with collagenase and 6 of 56 (10.7%) treated with open fasciectomy recurred. The use of open fasciectomy compared with collagenase injections to treat contracture was associated with a 74.2% decrease in the likelihood of recurrence. CONCLUSIONS: This study found that treatment of DD with collagenase injection is associated with a significantly lower degree of deformity correction, lower rate of resolution, and increased rate of recurrence when compared with open fasciectomy.

Long-term recurrence of Dupuytren's disease treated with clostridium histolitycum collagenase. Surgical treatment and anatomopathological study.

OBJECTIVE: To present the functional results obtained and the possible surgical difficulties after the surgical treatment of Dupuytren's disease (DD) recurrence in patients previously treated with Clostridium histolyticum (CCH) collagenase. MATERIALS AND METHODS: In this prospective study, 178 patients with DD were treated with CCH from 2011 to 2018; During long-term postoperative follow-up, 34 patients (19.1%) had recurrence of DD. In all patients injected in the IFP the disease recurred; In patients injected in the MCP, recurrence was highest in grade III and IV of the Tubiana classification, with involvement of the 5th finger and the two-finger Y-chord. Fourteen patients (7,8%) required surgery by partial selective fasciectomy due to recurrence of cord DD infiltration. The clinical and functional results of the patients, the difficulty of the surgical technique and the anatomopathological analysis of the infiltrated cords were evaluated in comparison with those of cords and patients who had had no previous CCH treatment. RESULTS: In all patients, cord rupture was achieved after injection, reducing joint contracture. In 14 patients, we observed during the follow-up the existence of DD recurrence that required surgical treatment by selective partial fasciectomy. There were no major difficulties in surgery and good clinical and functional results at 6 months of follow-up. The anatomopathological study of the resected tissue did not present histological alterations with respect to the samples obtained from patients initially treated by selective partial fasciectomy. CONCLUSIONS: Selective fasciectomy after CCH injection does not lead to important operative difficulties, as long as the CCH injection is performed according to the recommendations. There were no histological changes in the tissue after CCH injection. LEVEL OF EVIDENCE: III.

Incremental Treatment Response by Cycle With Collagenase Clostridium Histolyticum for Peyronie's Disease: A Pooled Analysis of Two Phase 3 Trials.

OBJECTIVE: To evaluate cumulative and incremental changes in penile curvature after each treatment cycle of collagenase clostridium histolyticum (CCH) in men with Peyronie's disease (PD). METHODS: Data from 2 phase 3, randomized, placebo-controlled trials were analyzed post hoc. Treatment was administered in up to 4 treatment cycles (per cycle: 2 injections, 1-3 days apart, of CCH 0.58 mg or placebo; subsequent penile modeling) at 6-week intervals. Penile curvature was measured at baseline and after each treatment cycle (weeks 6, 12, 18, and 24). Successful response was defined as ≥20% reduction from baseline penile curvature. RESULTS: Overall, 832 men (CCH, n = 551; placebo, n = 281) were included in the analysis. After each cycle, mean cumulative percent reduction from baseline penile curvature was significantly greater with CCH vs placebo (P <.001). Following one cycle, 29.9% of CCH recipients exhibited a successful response. Among nonresponders, additional cycles of injections led to further successful responses: 60.8% of first cycle failures achieved response after fourth cycle (8 injections), 42.7% of cycle 1-2 failures achieved response after fourth cycle, and 23.5% of cycle 1-3 failures achieved response after fourth cycle. CONCLUSION: Data showed incremental benefits from each of the 4 CCH treatment cycles. Completion of a full series of 4 CCH treatment cycles may optimize improvements in penile curvature in men with PD, including among those who did not clinically respond to previous treatment cycles.

Acute Lower Back Pain after Intralesional Injection of Collagenase Clostridium histolyticum for Peyronie's Disease.

PURPOSE: The safety label for collagenase Clostridium histolyticum was updated to include postinjection acute lower back pain as an adverse event observed with intralesional therapy for Peyronie's disease. Incidence and causality are unknown. We assessed frequencies and temporal associations for this adverse event in a large cohort. MATERIALS AND METHODS: Data on all men undergoing collagenase injections for Peyronie's disease at our institution from October 2015 through December 2020 were retrospectively assessed. The study included 330 patients, 300 completing at least 1 full course (8 injections). Measured outcomes included incidence and timing of back pain, and associations with demographics and comorbidities. RESULTS: Of 330 patients, 19 (5.8%) experienced at least 1 episode of postinjection acute lower back pain. Of 300 who completed at least 1 full course of 8 injections, 4 (1.3%) reported back pain within the 8-injection course. A subset underwent additional rounds (16 or 24 injections). Back pain increased to 8.7% (13/149) during a second round, 6.9% (3/43) during a third. No association was found with age, diabetes or back pain history. Most cases occurred shortly after injection; all were self-limited or resolved with a single dose of ketorolac. CONCLUSIONS: This single-center, retrospective analysis suggests that intralesional collagenase injections for Peyronie's disease may cause acute lower back pain in up to 6% of patients. Patients may benefit from counseling regarding this risk. Incidence rises with additional rounds of treatment. Prospective safety data regarding >8 injections do not exist. No patient had long-term sequelae of back pain.

Factors Associated with the Development, Progression, and Outcome of Dupuytren Disease Treatment: A Systematic Review.

BACKGROUND: The factors typically considered to be associated with Dupuytren disease have been described, such as those in the "Dupuytren diathesis." However, the quality of studies describing them has not been appraised. This systematic review aimed to analyze the evidence for all factors investigated for potential association with the development, progression, outcome of treatment, or recurrence of Dupuytren disease. METHODS: A systematic review of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature databases was conducted using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant methodology up to September of 2019. Articles were screened in duplicate. Prognostic studies were quality assessed using the Quality in Prognosis Study tool. RESULTS: This study identified 2301 records; 51 met full inclusion criteria reporting data related to 54,491 patients with Dupuytren disease. In total, 46 candidate factors associated with the development of Dupuytren disease were identified. There was inconsistent evidence between the association of Dupuytren disease and the presence of "classic" diathesis factors. The quality of included studies varied, and the generalizability of studies was low. There was little evidence describing the factors associated with functional outcome. CONCLUSIONS: This systematic review challenges conventional notions of diathesis factors. Traditional diathesis factors are associated with disease development and recurrence, although they are not significantly associated with poor outcome following intervention based on the current evidence.

Collagenase Tenotomy for Dupuytren Boutonniere.

SUMMARY: Treatment of boutonniere Dupuytren disease is rare and is resistant to treatment because of altered tendon dynamics. The authors used a small dose of collagenase clostridium histolyticum for an enzymatic tenotomy of the distal interphalangeal joint and showed that hyperextension at the distal interphalangeal joint improved significantly. Fifteen patients with boutonniere Dupuytren disease with severe proximal interphalangeal joint contractures averaging -69 degrees of extension were included in the study. Ten patients had at least one previous intervention, including surgical fasciectomy, Digit Widget treatment, and needle aponeurotomy. Collagenase clostridium histolyticum enzymatic tenotomy was performed in-office as a wide-awake procedure. All patients received varying doses of collagenase clostridium histolyticum for volar Dupuytren disease enzymatic fasciotomy and 0.1 mg of collagenase clostridium histolyticum into the distal extensor tendon for tenotomy to treat boutonniere deformity at the same time. Collagenase clostridium histolyticum enzymatic tenotomy significantly improved total active motion of the finger by 41.0 degrees (p = 0.001). Loss of extension at both the metacarpophalangeal joint and the proximal interphalangeal joint also improved with gains of 11.7 (p = 0.04) and 20.7 degrees (p = 0.0005) of extension, respectively. The average distal interphalangeal joint hyperextension was improved from 29.7 degrees to 14.0 degrees (p = 0.002). The authors show that collagenase injection led to significant average improvement in joint contracture at all finger joints and significantly increased the arc of motion at the proximal interphalangeal joint and metacarpophalangeal joint. Although collagenase has been previously used for flexion contractures in Dupuytren disease, we believe it has a role in treating the distal interphalangeal joint hyperextension deformity associated with boutonniere deformity in Dupuytren disease as well. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

A Phase I Clinical Trial to Assess Safety and Tolerability of Injectable Collagenase in Women with Symptomatic Uterine Fibroids.

Uterine fibroids feature excessive deposition of types I and III collagen. Previous ex vivo studies showed an FDA-approved collagenase (EN3835)-digested types I and III collagen fibers in fibroid tissues; however, collagenase had not been evaluated in vivo for effects on uterine fibroids. The objective was to assess the safety and tolerability of collagenase injection directly into uterine fibroids. This was a prospective, open label, dose escalation study. The study participants were fifteen women aged 35-50 years with symptomatic uterine fibroids planning to undergo hysterectomy. Three subjects received saline and methylene blue, three subjects received a fixed dose of EN3835, and 9 subjects received stepped, increasing dosages of EN3835, all by transvaginal, ultrasound-guided injections. Primary outcome measures were safety and tolerability of the injection and change in collagen content between treated and control tissues. There were no significant adverse events following injection of EN3835 into uterine fibroids. Masson's trichrome stains revealed a 39% reduction in collagen content in treated samples compared to controls (p <0.05). Second harmonic generation (SHG) analysis showed treated samples to have a 21% reduction in density of collagen compared to controls. Picrosirius-stained collagenase-treated fibroids showed collagen fibers to be shorter and less dense compared to controls. Subjects reported a decrease in fibroid-related pain on the McGill Pain Questionnaire after study drug injection in Group 2 at both 4-8 days and 60-90 days post-injection. The findings indicated that injection of collagenase was safe and well tolerated. These results support further clinical investigation of collagenase as a minimally invasive treatment of uterine fibroids. NCT0289848.

Conservative Therapy for Peyronie's Disease: a Contemporary Review of the Literature.

PURPOSE OF REVIEW: To analyze the literature on current conservative treatment options for Peyronie's disease (PD). RECENT FINDINGS: Conservative therapy with intralesional collagenase clostridium histolyticum (CCH) is safe and efficacious in either the acute or chronic phases of PD. Combination treatment with penile traction therapy (PTT) can produce even better results. While most PTT devices require extended periods of therapy up to 8 h per day, the RestoreX® device can be effective at 30-90 min per day. A variety of conservative therapies are available for treatment of PD. The available literature does not reveal any treatment benefit of oral therapies. Intralesional therapy is the mainstay conservative treatment of PD. Intralesional CCH therapy is the first Food and Drug Administration-approved intralesional therapy and represents the authors' preference for medical therapy. The most effective conservative management of PD likely requires a combination of therapies.

The Management of Penile Fracture: a Review of the Literature with Special Consideration for Patients Undergoing Collagenase Clostridium Histolyticum Injection Therapy.

PURPOSE OF REVIEW: To review the current literature on acute management of traumatic penile fracture, with a specific discussion of those injuries following collagenase clostridium histolyticum (CCH) injections for the treatment of Peyronie's disease. RECENT FINDINGS: The immediate repair of traumatic penile fracture injury is associated with significantly better prognosis for long-term sexual health. Corporal disruption following CCH administration has several distinct features, and the trend is to manage these patients conservatively in the absence of urethral injury. Traumatic penile fracture repair continues to have excellent results when performed immediately following injury. The post-CCH treatment setting portends increased difficulty during surgical management and can be successfully managed in most cases by conservative measures.

Health Care Spending in Patients With Stage 3 and Stage 4 Pressure Injuries and Patients With Diabetic Foot Ulcers Treated Early With Clostridial Collagenase Ointment: A Retrospective Data Review.

INTRODUCTION: Clostridial collagenase ointment (CCO) is the only enzymatic agent indicated for debriding chronic dermal ulcers that is approved by the United States Food and Drug Administration. OBJECTIVE: The objective of this study is to estimate health care spending among patients with Stage 3 and Stage 4 pressure injuries (PIs) and patients with diabetic foot ulcers (DFUs) who experienced early (ie, within 30 days of index diagnosis) versus late (31 to 90 days of index diagnosis) initiation of CCO. METHODS: Patients with PIs and DFUs between January 2007 and March 2017 were identified. One-to-one matched cohorts were used to compare all-cause health care spending and disease-related health care spending between the early initiation and late initiation groups. RESULTS: Compared to the early CCO initiation group, all-cause health care spending for the late CCO initiation group was higher in both patients with PIs and in patients with DFUs within the 12-month follow-up period. Compared to the early CCO initiation group, disease-related health care spending for the late CCO initiation group was higher in both patients with PIs and in patients with DFUs within the 12-month follow-up period. All computations were statistically significant. CONCLUSIONS: Early initiation of CCO provides both all-cause and disease-related health care savings to payers and persons managing patients with PIs or DFUs. Payers, providers, and facilities should consider mechanisms to encourage the early use of CCO to lower costs.

Human Pharmacokinetics and Safety of Subcutaneous Collagenase Clostridium Histolyticum in Women.

BACKGROUND: Clostridium collagenase histolyticum (CCH) is being evaluated in women as a cellulite treatment. OBJECTIVE: To report preclinical safety and human pharmacokinetics (PK) and safety data for CCH. METHODS: Across 3 PK studies, 41 women received 12 subcutaneous injections per thigh/buttock in 1 session (up to 3.36 mg/dose). Blood samples were taken at baseline; at 5, 10, 20, and 30 minutes postdose; and at 1, 2, 4, 8, 12, 24, 48, 168, and 504 hours postdose. In a preclinical study, rats received 0, 0.029, 0.13, or 0.29 mg/dose of CCH intravenously (IV) every other day (QOD) for 16 days (total, 8 doses) and were evaluated for histopathologic changes. RESULTS: In human PK studies, no quantifiable plasma concentrations of AUX-I or AUX-II were observed postdose (n= 39 evaluable). Adverse events were injection site–related (bruising [97.6%], pain [87.8%], and edema/swelling [46.3%]). Antidrug antibodies were seen in most women at 504 hours postdose. In rats, plasma concentrations of AUX-I and AUX-II (CCH components) were measurable for 30 minutes and 1-2 hours, respectively, after IV administration. At ≥43× proposed human therapeutic dose on a mg/kg basis, rats experienced elevated liver enzyme levels, increased liver weights, and histologic changes that were mostly reversed during a 14-day recovery period. CONCLUSIONS: In human studies, no quantifiable circulating CCH levels were observed after a single subcutaneous dose of CCH up to 3.36 mg. Preclinical data indicated that repeat IV dosing (QOD; 8 doses) at ≥43× proposed human dose on a mg/kg basis for CCH was generally well tolerated.J Drugs Dermatol. 2020;19(9):852-856. doi:10.36849/JDD.2020.5048THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Insights Into the Pathophysiology of Cellulite: A Review.

BACKGROUND: The etiology of cellulite is unclear. Treatment of cellulite has targeted adipose tissue, dermis, and fibrous septae with varying degrees of success and durability of response. OBJECTIVE: Results from clinical trials that target different anatomical aspects of cellulite can provide insights into the underlying pathophysiology of cellulite. MATERIALS AND METHODS: A search of the PubMed database and ClinicalTrials.gov website was conducted to identify clinical trials that have investigated treatments for cellulite. RESULTS: A lack of trial protocol standardization, objective means for quantification of improvement and reported cellulite severity, and short-term follow-up, as well as variation in assessment methods have made comparisons among efficacy studies challenging. However, the lack of durable efficacy and inconsistency seen in clinical results suggest that dermal or adipose tissue changes are not the primary etiologies of cellulite. Clinical studies targeting the collagen-rich fibrous septae in cellulite dimples through mechanical, surgical, or enzymatic approaches suggest that targeting fibrous septae is the strategy most likely to provide durable improvement of skin topography and the appearance of cellulite. CONCLUSION: The etiology of cellulite has not been completely elucidated. However, there is compelling clinical evidence that fibrous septae play a central role in the pathophysiology of cellulite.

Long-term Curvature Deformity Characterization in Men Previously Treated With Collagenase Clostridium Histolyticum for Peyronie's Disease, Subgrouped by Penile Plaque Calcification.

OBJECTIVE: To examine the long-term (5-year) efficacy and safety of collagenase clostridium histolyticum (CCH) therapy in men with Peyronie's disease and varying degrees of plaque calcification. MATERIALS AND METHODS: CCH-treated adult men from the 12-month Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies I/II or 9-month open-label studies were eligible. Degree of plaque calcification (no calcification, noncontiguous stippled calcification, or calcification that did not interfere with CCH injection) was determined by penile x-ray or ultrasound. Penile curvature deformity and Peyronie's Disease Questionnaire responses were assessed annually for up to 5 years, with ≥6 months between consecutive visits. RESULTS: For no calcification group, from baseline to last (Reference) visit during the prior studies (n = 160), mean penile curvature improved by 20.9° ± 16.3° (39.3%) with CCH. Similar improvements with CCH from baseline to Reference were observed in stippled calcification (n = 27; improvement of 24.1° ± 20.2° [42.7%]) and calcification (n = 27; improvement of 21.7° ± 14.8° [43.3%]) subgroups. At Year 5 follow-up in no calcification group (n = 119), an additional 10.0% improvement in mean penile curvature vs Reference (4.3°) occurred. Penile curvature improvements seen at Reference in stippled calcification and calcification groups were maintained through Year 5. Additional numeric improvements in 3 Peyronie's Disease Questionnaire domains were observed at Year 5 visit vs baseline scores. No long-term safety issues were identified. CONCLUSION: This first report of long-term (5-year) CCH clinical trial outcomes in a population with penile plaque calcification demonstrates that nonsurgical intralesional CCH therapy is an appropriate Peyronie's disease treatment in men with penile plaque calcification that is stippled or does not impede CCH injection.

Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute Phase Peyronie's Disease: A Multi-institutional Analysis.

OBJECTIVE: To study, in a multi-institutional setting, the efficacy/safety outcomes in acute phase Peyronie's disease (PD) of multiple high-volume centers employing CCH to treat PD, which is defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis. It is a chronic condition that afflicts 3%-13% of the US male population. There is no current multi-institutional research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD. METHODS: Retrospective data were collected for consecutive patients with PD who underwent treatment with CCH between April 2014 and March 2018 at 5 institutions. 918 patients were included. Patients with duration of PD no longer than 6 months at presentation qualified as being in the acute phase of PD. Main outcomes of interest include the change in curvature after receiving CCH therapy, and frequency of serious treatment-related adverse events. Successful improvement in curvature is defined as an at least 20% decrease in penile curvature from baseline after CCH therapy. RESULTS: A total of 918 patients were included in the analysis, of which 134 (14.6%) qualified as acute phase PD (group 1) and the remaining 784 (85.4%) qualified as stable phase (group 2). Mean duration of PD was 4.44 ± 1.68 months for group 1, and 40.8 ± 61.2 months for group 2. There was no significant difference in final change in curvature between acute and stable phase of PD (13.5° vs 15.6°, P = .09). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (16 patients, 11.9%) and the stable phase (77 patients, 9.8%; P = .44). In our multivariate analysis, only number of CCH cycles received was predictive of improvement of curvature. CONCLUSION: This large multi-institutional analysis confirms that CCH therapy is as safe and efficacious in acute phase PD as it is in stable phase PD.