Characteristics in patients with very early therapeutic response of condoliase chemonucleolysis for lumbar disc herniation.

INTRODUCTION: Treatment of lumbar disc herniation (LDH) using condoliase chemonucleolysis (CC) requires more time than surgery to demonstrate therapeutic effects. This study aimed to identify patients who show significant improvement in leg pain very early after CC and to determine pretreatment factors that can predict a very early therapeutic response. METHODS: The study included 52 patients who underwent CC for treatment-resistant LDH. Scores for low back and leg pain measured by a numerical rating scale were assessed at four time points (1 day, 1 week, 1 month, and 3 months after CC). Patients who reported subjective pain relief the day after treatment and further exhibited an improved straight leg raising (SLR) angle compared to pretreatment were classified as "very early responders (VER)". RESULTS: Of the 52 patients, 39 (75%) were VER, and 13 (25%) were non-VER. The VER showed earlier improvement in leg pain. The VER had a significantly higher proportion of positive SLR test patients (p = 0.01) and a significantly smaller pretreatment SLR angle compared to the non-VER (VER vs. non-VER: 40.6 ± 19.0 vs. 63.1 ± 16.9, p < 0.001). There were no significant differences in the level, type, and size of LDH and the disc regression rate between the two groups. CONCLUSIONS: Patients with a smaller pretreatment SLR angle are more likely to experience very early or early symptomatic relief, with a significant and sustained reduction in leg pain up to 3 months after CC treatment.

MRI characteristics of disc degeneration after condoliase injection in young patients: A consecutive case series.

BACKGROUND: Lumbar disc herniation (LDH) results in low back pain due to nerve root compression caused by nucleus pulposus degeneration. Chemonucleolysis of the nucleus pulposus by injection of condoliase is less invasive than surgery, but may cause disc degeneration. The purpose of the study was to examine outcomes of condoliase injection in patients in their teens and twenties using Pfirrmann criteria on MRI. METHODS: A single-center retrospective study was performed in 26 consecutive patients (19 men, 7 women) who underwent condoliase injection (1 mL, 1.25 U/mL) for LDH and had MRI scans at 3 and 6 months. Cases with and without an increase in Pfirrmann grade at 3 months post-injection were included in groups D (disc degeneration, n = 16) and N (no degeneration, n = 10). Pain was measured on a visual analogue scale (VAS). MRI findings were evaluated using the % change in disc height index (ΔDHI). RESULTS: The mean age of the patients was 21.1 ± 4.1 years and 12 were <20 years old. At baseline, 4, 21 and 1 were in Pfirrmann grades II, III and IV. In group D, no case had a further increase in Pfirrmann grade from 3 to 6 months. Pain significantly decreased in both groups. There were no adverse events. MRI showed a significant decrease in ΔDHI from 100% pre-injection to 89.4 ± 9.7% at 3 months in all cases (p < 0.05). There was a significant recovery in ΔDHI in group D from 3 to 6 months (85.4 ± 9.3% vs. 86.7 ± 9.1%, p < 0.05). CONCLUSIONS: These results suggest that chemonucleolysis with condoliase is effective and safe for LDH in young patients. Progression of Pfirrmann criteria at 3 months post-injection occurred in 61.5% of cases, but disc degeneration showed recovery in these patients. A longer-term study of the clinical symptoms related to these changes is required.

Short-term clinical and radiographic outcomes of chemonucleolysis with condoliase for painful lumbar disc herniation and analysis regarding intradiscal injection area.

Percutaneous chemonucleolysis with condoliase has been available for painful lumbar disc herniation since 2018 in Japan. This study investigated clinical and radiographic outcomes three months after the administration because the secondary surgical removal is most required during this period for the insufficient pain relief, and analyzed whether the differences of intradiscal injection areas affected the clinical outcomes. We retrospectively investigated 47 consecutive patients (males, 31; median age, 40 years) three months after the administration. Clinical outcomes were evaluated using the Japanese Orthopaedic Association Back Pain Questionnaire (JOABPEQ), a visual analog scale (VAS) score for low back pain, and VAS scores for pains and numbness in the lower limbs. Radiographic outcomes were analyzed in 41 patients, using parameters such as mid-sagittal disc height and maximal protrusion length of herniation on MRI preoperatively and at the final follow-up. Postoperative median evaluation period was 90 days. The effective rate of low back pain based on the pain-related disorders at baseline and the last follow-up in the JOABPEQ reached 79.5%. The postoperative proportion of VAS scores recovery ≥ 2 points and ≥ 50% for pains in the lower limbs were 80.9% and 66.0%, respectively, revealing satisfactory effectiveness. Preoperative median mid-sagittal disc height significantly reduced from 9.5 to 7.6 mm postoperatively. There were no significant differences in pain relief in the lower limbs by injection areas in the center and the dorsal 1/3rd near the herniation of nucleus pulposus. Chemonucleolysis with condoliase revealed satisfactory short-term outcomes after the administration regardless of intradiscal injection areas.

Condoliase chemonucleolysis for lumbar disc herniation: A post-hoc follow-up study of patients in previous clinical trials.

BACKGROUND: Chemonucleolysis with condoliase significantly improved clinical symptoms in patients with lumbar disc herniation. We evaluated the surgical intervention rate and outcomes for >1 year after condoliase treatment. METHODS: This was a follow-up study of patients who received condoliase or placebo in two previous randomized, placebo-controlled clinical trials with 1-year follow-ups. A post-treatment surgery survey and on-site examination were administered and patients' data from the clinical trial records and additional interview data were analyzed to evaluate the surgical intervention rate. Patients' lumbar disease symptoms, Oswestry Disability Index, and imaging features were evaluated. RESULTS: Among the patients (condoliase, n = 228; placebo, n = 128) enrolled in the clinical trials, additional post-treatment surgery data were available for 231 patients after the clinical trials ended, and 179 patients underwent post-trial examinations, at least 5 years and 17 months after the end of the clinical trials. The surgical intervention rate in the placebo and condoliase groups was 20.7% (95% confidence interval: 14.2-29.7) and 13.4% (95% confidence interval: 8.8-20.2), respectively. The mean change in Oswestry Disability Index score from pre-injection in placebo and condoliase groups was -24.7 ± 15.0 and -32.7 ± 18.6 (between-group difference: -8.0 ± 17.3; 95% confidence interval: -13.2 to -2.7). Modic Type 2 changes were observed, particularly in the condoliase group. No relationship between lumbar disease symptoms and change in imaging features was found. CONCLUSIONS: This follow-up study more than 1 year revealed no new safety concerns of condoliase. However, because the study had several limitations, such as large loss of follow-up, further research is needed.

Factors associated with disc degeneration based on Pfirrmann criteria after condoliase treatment for lumbar disc herniation.

BACKGROUND: Lumbar disc herniation (LDH) is a common cause of low back pain and is associated with degeneration of the nucleus pulposus causing nerve root compression. Chemonucleolysis of the nucleus pulposus with condoliase is a low-invasive treatment for LDH. The purpose of this study was to investigate changes in Pfirrmann criteria, which are used to evaluate disc degeneration, after injection of condoliase into a herniated intervertebral disc, and to identify factors associated with disc degeneration at 3 months post-injection. METHODS: Medical records and radiographic findings were reviewed retrospectively for 127 patients with LDH (88 male, 39 female, mean age: 46.6 ± 17.1 years, mean follow-up: 9.8 ± 7.8 months) who underwent chemonucleolysis with intradiscal condoliase injection at our center since September 2018. Condoliase (1.25 U/mL; 1 mL volume) was injected toward the middle of the affected intervertebral nucleus pulposus using a 21-gauge disc-puncture needle. RESULTS: Cases in which the Pfirrmann grade did and did not progress in the 3 months after the injection were included in groups P (progression, n = 49) and NP (non-progression, n = 78), respectively. Logistic regression analysis of progression of Pfirrmann grade post-injection showed significant associations with age <40 years (p = 0.013, odds ratio (OR): 3.69, 95% confidence interval (CI): 1.32-10.31), Pfirrmann Grade II or III at baseline (p = 0.021, OR: 3.51, 95% CI: 1.24-9.64), and a high-intensity MRI signal in the herniation (p = 0.047, OR: 2.97, 95% CI: 1.03-8.87). Patients in group P had significantly higher rates of disc height decrease ≥20%, reduced herniated disc size, and improved VAS for pain, but both groups had significant decreases in pain. No cases had anaphylactic shock or neurologic sequelae. CONCLUSIONS: These results show the safety and efficacy of chemonucleolysis with condoliase for treatment of painful LDH. Progression of Pfirrmann criteria on MRI at 3 months after injection was significantly associated with an improved clinical outcome.

Intradiscal Condoliase Injection Therapy for Recurrent Lumbar Disc Herniation: Case Series and Literature Review.

Background and objectives: Although chemonucleolysis with condoliase for lumbar disc herniation (LDH) has become common, few reports have described its application in the treatment of recurrent LDH. Therefore, this study aimed to evaluate the safety and efficacy of condoliase treatment in six patients with recurrent LDH and review the available literature on condoliase treatment for LDH. Materials and Methods: Six patients (four men and two women; mean age, 64.7 years) with recurrent LDH who were treated with condoliase at our hospital between 2019 and 2022 were included. The clinical records and images of the patients were retrospectively evaluated. In addition, the available English literature on condoliase treatment for LDH was retrieved and reviewed. Results: Among the six patients included in the study, three showed >50% improvement in leg pain after treatment, which is a lower efficacy rate than that in previous reports. In addition, two patients required surgery after treatment, which is a higher rate than that in previous reports. The mean intervertebral disc height significantly decreased from 8.4 mm before treatment to 6.9 mm after treatment, consistent with the results of previous studies. None of the cases showed Modic type I changes on magnetic resonance imaging. Conclusions: Although the efficacy of condoliase treatment for recurrent LDH may be lower than that for primary LDH, this treatment was found to be safe and applicable for recurrent LDH.

Condoliase therapy for lumbar disc herniation -2 year clinical outcome.

BACKGROUND: Condoliase-induced chemonucleolysis is a less invasive treatment for lumbar disc herniation (LDH); however, its long-term clinical outcomes remain unclear. We investigated 2-year clinical outcomes and assess radiographs after chemonucleolysis with condoliase. METHODS: We enrolled patients with LDH who received condoliase therapy, with a minimum follow-up period of two years. Sixty-seven patients (44 men, 23 women; mean age, 46.7 ± 18.0 years) were analyzed. Time-course changes in disc height, disc degeneration, and herniation size were assessed. For clinical outcomes assessment, visual analog scale (VAS) scores for leg and back pain and the Oswestry disability index (ODI) were obtained at baseline and the 3-month, 1-year, and 2-year follow-ups. We obtained a questionnaire from these patients at two years to assess satisfaction and recommendation. Condoliase therapy was considered to be effective in patients whose VAS score for leg pain improved by ≥ 50% at 2 years from baseline and who did not require surgery. RESULTS: Condoliase therapy was effective in 51 patients (76.1%). Eight patients (11.9%) required surgery due to ineffectiveness of the therapy. Condoliase therapy was ineffective in five out of six patients with a history of discectomy. The ODI and VAS scores for leg and back pain significantly improved from three months to two years. Of the patients, 80% satisfied with their outcomes, and 85% recommended this therapy. Progression of disc degeneration was observed in 57.1% of patients at three months; however, 30% recovered to baseline at two years. The mean disc height decreased at three months, but recovered slightly at one year and remained stable until two years. No recurrent disc herniation was observed. CONCLUSIONS: Chemonucleolysis with condoliase was effective in 78% of patients with LDH for 2 years. Chemonucleolysis-induced disc degeneration was slightly recovered and maintained for two years post-injection. This treatment resulted in high patient satisfaction and recommendations.

Predictive Factors for Poor Outcome following Chemonucleolysis with Condoliase in Lumbar Disc Herniation.

Background and Objectives: Condoliase, a chondroitin sulfate ABC endolyase, is a novel and minimally invasive chemonucleolytic drug for lumbar disc herniation. Despite the growing number of treatments for lumbar disc herniation, the predicting factors for poor outcomes following treatment remain unclear. The aim of this study was to determine the predictive factors for unsuccessful clinical outcome following condoliase therapy. Material and Methods: We performed a retrospective single-center analysis of 101 patients who underwent chemonucleolysis with condoliase from January 2019 to December 2021. Patients were divided into good outcome (i.e., favorable outcome) and poor outcome (i.e., requiring additional surgical treatment) groups. Patient demographics and imaging findings were collected. Clinical outcomes were evaluated using the numerical rating scale and Japanese Orthopaedic Association scores at baseline and at 1- and 3-month follow-up. Pretreatment indicators for additional surgery were compared between the 2 groups. Results: There was a significant difference in baseline leg numbness between the good outcome and poor outcome groups (6.27 ± 1.90 vs. 4.42 ± 2.90, respectively; p = 0.033). Of the 101 included patients, 32 received a preoperative computed tomography scan. In those patients, the presence of calcification or ossification in disc hernia occurred more often in the poor outcome group (61.5% vs. 5.3%, respectively; p < 0.001; odds ratio = 22.242; p = 0.014). Receiver-operating characteristics curve analysis for accompanying calcification or ossification showed an area under the curve of 0.858 (95% confidence interval, 0.715−1.000; p = 0.001). Conclusions: Calcified or ossified disc herniation may be useful predictors of unsuccessful treatment in patients with condoliase administration.

Multicenter Retrospective Analysis of Intradiscal Condoliase Injection Therapy for Lumbar Disc Herniation.

Background and Objectives: Intradiscal injection of Condoliase (chondroitin sulfate ABC endolyase), a glycosaminoglycan-degrading enzyme, is employed as a minimally invasive treatment for lumbar disc herniation (LDH) and represents a promising option between conservative treatment and surgical intervention. Since its 2018 approval in Japan, multiple single-site trails have highlighted its effectiveness, however, the effect of LDH types, and influences of patient age, sex, etc., on treatment success remains unclear. Moreover, data on teenagers and elderly patients has not been reported. In this retrospective multi-center study, we sought to classify prognostic factors for successful condoliase treatment for LDH and assess its effect on patients < 20 and ≥70 years old. Materials and Methods: We reviewed the records of 137 LDH patients treated through condoliase at four Japanese institutions and assessed its effectiveness among different age categories on alleviation of visual analog scale (VAS) of leg pain, low back pain and numbness, as well as ODI and JOA scores. Moreover, we divided them into either a "group-A" category if a ≥50% improvement in baseline leg pain VAS was observed or "group-N" if VAS leg pain improved <50%. Next, we assessed the differences in clinical and demographic distribution between group-A and group-N. Results: Fifty-five patients were classified as group-A (77.5%) and 16 patients were allocated to group-N (22.5%). A significant difference in Pfirrmann classification was found between both cohorts, with grade IV suggested to be most receptive. A posterior disc angle > 5° was also found to approach statical significance. In all age groups, average VAS scores showed improvement. However, 75% of adolescent patients showed deterioration in Pfirrmann classification following treatment. Conclusions: Intradiscal condoliase injection is an effective treatment for LDH, even in patients with large vertebral translation and posterior disc angles, regardless of age. However, since condoliase imposes a risk of progressing disc degeneration, its indication for younger patients remains controversial.

Selective Chemonucleolysis With Condoliase in Cynomolgus Monkeys.

Selective chemonucleolytic effects of condoliase, a glycosaminoglycan degrading enzyme, was investigated histopathologically in cynomolgus monkeys. Condoliase was administered once into the lumber intervertebral disc (IVD), and as a comparative control, chymopapain, a proteolytic enzyme, was administered in a similar manner. Histopathological changes of the IVD and the adjacent vertebral body (VB) were examined at 1 to 26 weeks after administration. Major changes induced by condoliase in the IVD were degenerative and necrotic changes in the nucleus pulposus, annulus fibrosus, cartilaginous endplate (CEP), and epiphyseal growth plate (EGP); focal disappearance of the EGP; and neovascularization and ossification of the CEP. Decreased/necrosis of bone marrow cells with new bone formation was observed in the VB. Cellular regeneration in the IVD was observed as a recovery changes on and after week 4. The changes in the IVD and VB subsided at week 26. Chymopapain induced qualitatively similar but more widely extended changes. The degrees of the changes in the IVD and VB were more severe than those of condoliase, and the changes were exacerbated even at week 26. These results indicated that histopathological changes caused by condoliase were less severe and more selective than those by chymopapain.

Chemonucleolysis with Chondroitin Sulfate ABC Endolyase for Treating Lumbar Disc Herniation: Exploration of Prognostic Factors for Good or Poor Clinical Outcomes.

Background and Objectives: Chondroitin sulfate ABC endolyase (condoliase) was launched as a new drug for chemonucleolysis in 2018. Few studies assessed its clinical outcomes, and many important factors remain unclear. This study aimed to clarify the preoperative conditions in which condoliase could be highly effective. Materials and Methods: Of 47 patients who received condoliase, 34 were enrolled in this study. The mean age of the patients was 33 years. The average duration since the onset of disease was 8.6 months. We evaluated patients' low back and leg pain using a numerical rating scale (NRS) score at two time points (before therapy and 3 months after therapy). We divided the patients into two groups (good group (G): NRS score improvement ≥ 50%, poor group (P): NRS score improvement < 50%). The parameters evaluated were age, disease duration, body mass index (BMI), and positive or negative straight leg raising test results. In addition, the loss of disc height and preoperative radiological findings were evaluated. Results: In terms of low back and leg pain, the G group included 9/34 (26.5%) and 21/34 (61.8%) patients, respectively. Patients' age (low back pain G/P, 21/36.5 years) was significantly lower in the G group for low back pain (p = 0.001). High-intensity change in the protruded nucleus pulposus (NP) and spinal canal occupancy by the NP ≥ 40% were significantly high in those with leg pain in the G groups (14/21, p = 0.04; and 13/21, p = 0.03, respectively). Conclusions: The efficacy of improvement in leg pain was significantly correlated with high-intensity change and size of the protruded NP. Condoliase was not significantly effective for low back pain but could have an effect on younger patients.

Histological analysis of nucleus pulposus tissue from patients with lumbar disc herniation after condoliase administration.

Background: Condoliase is an enzyme used as a treatment for lumbar disc herniation (LDH). This enzyme degrades chondroitin sulfate (CS) in the nucleus pulposus of the intervertebral disc (IVD). However, there are cases in which symptoms do not improve, despite condoliase administration. This study reports histological analysis of lumbar disc tissue of LDH patients who underwent surgery because condoliase had no therapeutic effect. Methods: Between March 2019 and August 2019, 12 LDH patients who underwent full endoscopic spine surgery (FESS) discectomy at the Dezawa Akira PED Clinic were the subjects of the study. There are two study groups: six cases underwent FESS after condoliase administration, while six underwent FESS without condoliase administration. The average duration from drug administration to surgery was 152 days. Herniated disc removed at surgery was evaluated by histological staining including immunohistochemistry by anti-CS antibodies. Results: Multiple large clusters (40-120 µm in diameter) were observed in the nucleus pulposus of those who received condoliase, but no clusters were observed in those who did not. The lumbar disc tissues, including the nucleus pulposus of recipients, were stained with anti-CS antibodies that recognize the CS unsaturated disaccharide, but non-administration tissue was not stained. These findings suggest that the enzyme acted on the nucleus pulposus, even in cases where symptoms were not improved by condoliase administration. Furthermore, there was no histological difference between stained images of the extracellular matrix in those who did or did not receive condoliase, suggesting that condoliase acted specifically on CS in the nucleus pulposus. Conclusions: We demonstrated that CS in the nucleus pulposus was degraded in patients in whom condoliase did not have a therapeutic effect. Moreover, condoliase acts in human IVD without causing necrosis of chondrocytes and surrounding tissues.

Psychological Factors Can Affect the Clinical Outcome of Chemonucleolysis with Condoliase in Patients with Lumbar Disk Herniation.

Introduction: Condoliase-based chemonucleolysis is a minimally invasive intermediate treatment option between conservative approaches and surgical interventions for lumbar disk herniation (LDH). In this study, the effects of psychological factors on the clinical outcomes of condoliase therapy for LDH were assessed. Methods: This study involved patients with LDH who received condoliase injections over a 1-year follow-up period. Data from the visual analog scale (VAS) scores for leg and back pain, Oswestry Disability Index, and Hospital Anxiety and Depression Scale (HADS), which was utilized for the psychological assessment, were collected. Using magnetic resonance imaging, changes in disk height and degeneration were evaluated. Data were assessed at baseline and 1-month, 3-month, and 1-year follow-ups. Condoliase therapy was considered effective in patients whose VAS score for leg pain improved by ≥50% at 1 year from baseline and who did not require surgery. The patients were divided into two groups: those who reported effective treatment (Group E) and those who did not (Group I). Between these two groups, comparative analyses were carried out. Results: In this study, a total of 102 patients (70 men; mean age, 43.8±18.2 years) were included. Condoliase therapy was effective in 76 patients (74.5%). Thirty-five patients (34.3%) showed psychological factors (HADS-Anxiety [HADS-A]≥8 or HADS-Depression [HADS-D]≥8) preoperatively and had a significantly lower rate of effectiveness than did those without psychological factors. Group I demonstrated significantly higher baseline back pain VAS, HADS, and HADS-D scores when compared with Group E. Logistic regression analysis identified females and the baseline HADS-D score as independent factors that were related to the effectiveness of condoliase therapy. Conclusions: The patients with psychological factors tended to experience residual pain resulting in adverse effects on the clinical outcomes of chemonucleolysis with condoliase.

Immediate Effects, Detailed Clinical Outcomes, and Prognostic Factors of Chemonucleolysis Using Condoliase for Lumbar Disc Herniation.

Chemonucleolysis utilizing condoliase is a minimally invasive treatment for lumbar disc herniation (LDH) aimed at reducing intervertebral disc pressure and enhancing symptoms. In this study, lower limb pain was measured using the numeric rating scale (NRS) the day after treatment and 1 and 3 months after treatment. Prognostic factors were assessed, categorizing participants into an improvement group (I-group) for NRS lower limb pain scores of ≥3.5 and a non-improvement group (N-group) for scores of <3.5. This study included a total of 225 patients treated between April 2020 and March 2023. The mean age was 46.5 ± 16.5 years, with 151 males. The mean duration of illness was 6.2 ± 8.52 months. As of the day after treatment, 60 cases were classified into the I-group, 118 cases at 1 month after surgery, and 152 cases at 3 months after surgery. The disease duration before treatment was significantly shorter in the I-group at 1 (8.19 ± 8.74 [I-group] vs. 5.17 ± 8.04 [N-group] months) and 3 months (8.51 [I-group] ± 7.35 vs. 5.69 ± 8.87[N-group] months) after treatment. The comparison of baseline leg pain NRS shows a difference in leg pain NRS in the I-group when compared on the day after treatment (6.02 ± 2.64 [I-group] vs. 7.50 ± 1.79 [N-group]), 1 (5.13 ± 2.69 [I-group] vs. 7.58 ± 1.66 [N-group]), and 3 months (4.42 ± 2.70 [I-group] vs. 7.34 ± 1.77 [N-group]). Chemonucleolysis using condoliase for LDH can improve symptoms the day after treatment and can be a minimally invasive treatment to avoid surgery.

Changes in Intervertebral Disc Properties after Intradiscal Injection of Condoliase for Painful Lumbar Disc Herniation.

The detailed changes in disc properties after intradiscal injection of condoliase remain controversial. At 3 and 9 months after administration, radiographic changes in discs were investigated. A total of 41 patients (men, 25; median age, 46 years) who underwent regular follow-up magnetic resonance imaging at 3 and 9 months after administration without additional invasive therapy were retrospectively investigated. The intensity changes of the nucleus pulposus based on the Pfirrmann disc grading system, midsagittal disc height, and maximum protrusion length of herniation were assessed. In addition, disc height changes were compared between 24 patients aged <50 years (young group) and 17 patients aged ≥50 years (over 50s group). The overall mean disc heights were 9.1, 7.5, and 7.6 mm preoperatively, at 3 months, and at 9 months, respectively, with a significant reduction at 3 months (P < 0.001) and no significant changes thereafter. The mean maximum protrusion length of herniation significantly and gradually decreased. The overall proportions of Pfirrmann disc grades after administration were equivalent between 3 and 9 months. However, the recovery from Pfirrmann disc grades IV to III was confirmed in 8 of 17 cases (47.1%) between 3 and 9 months, whereas 6 of 20 cases (30.0%) showed a decline from III to IV. Patients in the young group with pretreatment disc height >11 mm had the greatest reduction in disc height than the over 50s group. In conclusion, the clinical outcomes in the over 50s group were comparable to those in the young group after injection of condoliase, whereas young patients with higher disc were more susceptible to disc height reduction.

Enzymatic chemonucleolysis for lumbar disc herniation-an assessment of historical and contemporary efficacy and safety: a systematic review and meta-analysis.

Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a non-surgical alternative. This systematic review and meta-analysis aims to assess the efficacy and safety of chemonucleolytic enzymes for LDH. The primary objective is to evaluate efficacy through "treatment success" (i.e., pain reduction) and severe adverse events (SAEs) rates. Additionally, differences in efficacy and safety trends among chemonucleolytic enzymes are explored. Following our PROSPERO registered protocol (CRD42023451546) and PRISMA guidelines, a systematic search of PubMed and Web of Science databases was conducted up to July 18, 2023. Inclusion criteria involved human LDH treatment with enzymatic chemonucleolysis reagents, assessing pain alleviation, imaging changes, and reporting on SAEs, with focus on allergic reactions. Quality assessment employed the Cochrane Source of Bias and MINORS tools. Meta-analysis utilized odds ratios (OR) with 95% confidence intervals (CI). Among 62 included studies (12,368 patients), chemonucleolysis demonstrated an 79% treatment success rate and significantly outperformed placebo controls (OR 3.35, 95% CI 2.41-4.65) and scored similar to surgical interventions (OR 0.65, 95% CI 0.20-2.10). SAEs occurred in 1.4% of cases, with slightly higher rates in chymopapain cohorts. No significant differences in "proceeding to surgery" rates were observed between chemonucleolysis and control cohorts. Limitations include dated and heterogeneous studies, emphasizing the need for higher-quality trials. Further optimization through careful patient selection and advances in therapy implementation may further enhance outcomes. The observed benefits call for wider clinical exploration and adoption. No funding was received for this review.

Indication and Limitation of Intradiscal Condoliase Injection for Patients with Lumbar Disc Herniation: Literature Review and Meta-Analysis.

Background: Intradiscal condoliase injection for lumbar disc herniation (LDH) was developed in Japan in 2018. The treatment is intermediate between conservative therapy and surgery, and its frequency is increasing. Condoliase is limited to a single application over a lifetime, rendering it important to understand the indications and predictors of its effectiveness. This review aimed to summarize published studies and provide appropriate indications and limitations for appropriate patient selection based on existing findings. Methods: While adhering to PRISMA guidelines, we searched the PubMed, Web of Science, and EMBASE databases to identify articles reporting the clinical outcomes of intradiscal condoliase injection for LDH. Data extraction focused on the effective rate, prognostic factors, and posttreatment imaging changes and was used in the meta-analysis. Results: Nineteen studies met the inclusion criteria. Our meta-analysis revealed 78% total response, 11% posttreatment surgery, and 42% posttreatment Pfirrmann-classification-grade progression rates. Posttreatment intervertebral disc degeneration was potentially associated with an improved response rate and disc regeneration one year posttreatment, especially in young patients. The Regimen for patients aged <20 and >70 years should be carefully selected, including those with a disease duration of >1 year, recurrent LDH, small-sized LDH, vertebral instability, and inadequate duration (<3 months) of conservative therapy. Conclusions: Although long-term outcomes and imaging changes must be evaluated owing to the heterogeneity of previous studies, intradiscal condoliase injection is a minimally invasive and cost-effective treatment option for patients with LDH. Treatment indications should be determined after carefully evaluating evidence from previous conservative and surgical treatments.

Comparison of Percutaneous Endoscopic Transforaminal Discectomy, Chemonucleolysis, Microdiscectomy, and Microendoscopic Discectomy for Symptomatic Lumbar Disc Herniation: One-year Follow-up Clinical Results and Disc Degeneration.

This study compared the 1-year clinical outcomes and disc degeneration rates after transforaminal full-endoscopic lumbar discectomy (TF-FED), condoliase injection, open discectomy (OD), and microendoscopic discectomy (MED) for lumbar disc herniation (LDH). In total, 279 patients with LDH were divided into four treatment groups: TF-FED, OD, MED, and condoliase injection. Outcomes were evaluated on the basis of the complication rate, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), visual analog scale (VAS) scores, and the modified MacNab criteria. Surgical and hospital costs were assessed. Disc degeneration and endplate bone marrow edema were evaluated using magnetic resonance images. The mean postoperative JOABPEQ, VAS, or modified MacNab scores among the four groups had no significant differences. Additionally, the nerve injury or reoperation rate among the TF-FED, OD, and MED groups had no significant difference. However, the reoperation rate with condoliase injection was high because of residual disc herniation. Surgical and hospital costs were lower with condoliase injection and higher with OD and MED than those with TF-FED. With TF-FED and condoliase injection, the Pfirrmann grade progressed, and the disc height was significantly smaller than that with OD and MED. Endplate bone marrow edema was more common with condoliase injection and TF-FED. All groups had good outcomes. TF-FED and condoliase injection may reduce the burden of surgery because they can be performed under local anesthesia with little blood loss and low medical costs but tend to be associated with disc degeneration and endplate bone marrow edema. A randomized controlled study with a larger sample is needed.

A Phase 3, Randomized, Double-Blind, Sham-Controlled Trial of SI-6603 (Condoliase) in Patients With Radicular Leg Pain Associated With Lumbar Disc Herniation.

BACKGROUND CONTEXT: SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH. PURPOSE: The Discover 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH. STUDY DESIGN/SETTING: A randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States. PATIENT SAMPLE: Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks. OUTCOME MEASURES: The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings. METHODS: Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery. RESULTS: Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=0.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=0.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=0.0223) and Week 52 (p=0.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred. CONCLUSIONS: Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies.

Biochemical and crystallographic assessments of the effect of 4,6-O-disulfated disaccharide moieties in chondroitin sulfate E on chondroitinase ABC I activity.

O-sulfated N-acetyl-d-galactosamine (GalNAc) residues in chondroitin sulfate (CS) play a crucial role in chondroitinase ABC I (cABC-I) activity. CSA containing mainly 4-O-monosulfated GalNAc was a good substrate for the enzyme, but not CSE containing mainly 4,6-O-disulfated GalNAc [GalNAc(4S,6S)]. Each CS isomer exhibits structural heterogeneity; CSE has di-sulfated disaccharide units and mono-sulfated disaccharide units. Disaccharide composition analysis of digested products revealed that mono-sulfated disaccharide units in CSE contributed to the enzyme reactivity. Although enough substrate (CSA) was present in mixtures of CSA and CSE for reaction, the reactivity was reduced depending on the amount of CSE in the mixture. These results suggested that CSE is not only resistant to enzyme digestion but also attenuates enzyme activity. To understand the mechanism of action, crystallography of cABC-I in complex with unsaturated CSE-disaccharide, ΔDi-(4,6)S, was performed. Both 4-O- and 6-O-sulfate groups in ΔDi-(4,6)S interact with Arg500, suggesting that there was a greater interaction between ΔDi-(4,6)S and Arg500 than between mono-sulfated disaccharides and Arg500. Besides, this interaction attenuated enzyme activity by interfering with a function of Arg500, which is the charge neutralization of the carboxy group of D-glucuronic acid (GlcA) residues in CS. When interacting with the CSE-disaccharide unit [GlcAß1-3GalNAc(4S,6S)] in CS, cABC-I cannot interact with other CS-disaccharide units until it has digested the CSE-disaccharide unit. The low reactivity of cABC-I with CSE is attributable to two suggested factors: (a) resistance of E-units in CSE molecules to digestion by cABC-I, and (b) tendency of E-units in CSE molecules to attenuate cABC-I activity.