Osteoarthritis (OA) is the most prevalent type of joint disorder, primarily affecting the hips, knees, hands, and feet. Various treatment options are available for OA patients, with intra-articular injections commonly used to enhance local effects while reducing systemic side effects. These injections include corticosteroids, analgesics, anti-inflammatory medications, cross-linked collagen, anti-cytokine agents, and hyaluronic acid (HA) [1,2]. Recently, the intra-articular injection of polydeoxyribonucleotide (PDRN) has gained attention. PDRN is a polymer molecule capable of binding a large number of water molecules, with the potential to reorganize the surface cartilage structure by aligning and regulating water molecules using a three-dimensional gel [3,4]. When injected into the joint, PDRN can supply moisture to the joint surface [4]. Therefore, previous studies have suggested that PDRN may serve as a superior treatment compared to HA, given its strong chondroprotective effects [5]. In studies comparing the efficacy and safety of PDRN and HA for intra-articular injections, no significant differences have been observed in terms of efficacy or safety [6-8]. Consequently, intra-articular PDRN injections could be a useful alternative to HA injections for treating OA.

According to the literature, several pseudoseptic reactions following intra-articular HA injections have been reported in the literature [9]. In addition to HA, pseudoseptic reactions have also been documented after intra-articular injections of other agents, such as platelet-rich plasma [10]. However, there have been no reports of adverse reactions following intra-articular PDRN injections. In this case report, we aim to share a case of pseudoseptic reaction that occurred following an intra-articular PDRN injection in the ankle.

An 81-year-old male patient presented to the pain clinic (tertiary medical center) with complaints of worsening bilateral leg and foot pain that had been persisting for six months. His medical history included hypertension, chronic kidney disease, and two lumbar surgeries at the L3-4 level 15 years ago.

The patient described the pain as stabbing, with a Visual Analog Scale (VAS) score of 9, particularly severe on the medial sides of both ankles. Despite receiving multiple neuraxial and peripheral nerve blocks at another hospital, relief was minimal. He was also taking Non-steroidal anti-inflammatory drugs (NSAIDs) and Tramadol, but with no significant improvement, leading to his referral to a tertiary medical center.

On physical examination, the straight leg raise test was positive bilaterally at 40 degrees, and there was tenderness around the lumbar spinous processes from L2 to L4. Tenderness was also noted over both medial malleoli. Diagnostic evaluation, including lumbar spine X-ray, ankle X-ray, lumbar MRI, and electromyography (EMG) of the lower extremities, was planned.

Upon returning three weeks later, imaging studies showed retrolisthesis at L1-2, L2-3, and Grade 1 spondylolisthesis at L4-5, with underlying degenerative spondylosis. EMG results suggested left S1 radiculopathy with mild partial axonotmesis without recent denervation potentials. Ankle X-rays revealed osteoarthritis in both talocrural joints. To manage the ankle pain, 1 ampoule (3 ml) of PDRN (Polydeoxynucleotide Na, 5.625 mg) was injected into each ankle (Fig. 1A).

Figure 1. Ultrasound images showing intra-articular polydeoxyribonucleotide (PDRN) injections in the ankle: (A) first injection; (B) second injection. Arrows indicate needle entry points.

Four weeks later, the patient returned, reporting a mild improvement in symptoms, though ankle pain persisted, with a VAS score of 7. A second injection of PDRN was administered to both ankles (Fig. 1B).

However, 10 days later, the patient visited the emergency room with left ankle pain, which had started seven days after the second injection. He experienced severe pain with difficulty walking and presented with a fever of 38.6°C. Physical examination revealed tenderness, swelling, redness, and warmth in the left ankle, with restricted range of motion due to pain. Laboratory results showed elevated WBC 10,170/μl and hs-CRP 7.51 mg/dl. MRI revealed nonspecific synovitis with moderate effusion in the left talocrural joint (Fig. 2). The synovial fluid was turbid and yellowish, with a WBC count of 36,000/mm³ (95% polymorphonuclear cells), indicating an inflammatory process. Based on these findings, septic arthritis was suspected, and the patient was admitted for orthopedic surgery.

Figure 2. Sagittal view of T2-weighted magnetic resonance images of the left ankle taken in the emergency room, showing nonspecific synovitis with moderate effusion in the left talocrural joint (arrows).

The following day, arthroscopic debridement was performed due to a suspicion of septic arthritis (Fig. 3). Intraoperatively, joint fluid with a crystal-like appearance was observed, and tenosynovectomy of the flexor hallucis longus was performed due to tenosynovitis and fluid collection seen on MRI.

Figure 3. Intraoperative photograph of the ankle taken during surgery.

However, the synovial fluid was negative for crystals under polarized microscopy, ruling out crystal-induced arthropathy. No microorganisms were detected on gram stain or culture from the surgical specimen. After five days of empirical antibiotic (Cefazolin) therapy, the antibiotics were discontinued, and the patient showed improvement. He was discharged on the sixth postoperative day without any complications.

At a follow-up visit two weeks after discharge, the patient reported significant improvement in pain, allowing for normal daily activities. The surgical stitches were removed, and further monitoring was planned for continued follow-up.

Osteoarthritis (OA) is the most prevalent joint disorder, predominantly affecting the hips, knees, hands, and feet. A wide range of treatment options exist for managing OA, including intra-articular injections aimed at enhancing localized therapeutic effects while minimizing systemic side effects. These injections typically involve corticosteroids, analgesics, anti-inflammatory agents, cross-linked collagen, anti-cytokine drugs, or hyaluronic acid (HA), and are collectively referred to as viscosupplementation [1].

Intra-articular HA injections are straightforward procedures and are widely employed for the treatment of mild to moderate OA [2]. HA works by improving the viscoelasticity of the synovial fluid, providing lubrication to the joint surfaces, reducing friction, and protecting cartilage from mechanical wear. This helps preserve the elasticity of the joint and offers sustained pain relief [11]. Despite numerous studies supporting HA’s therapeutic benefits, there remains ongoing debate about its overall effectiveness, particularly regarding long-term pain relief. A systematic review and network meta-analysis reported uncertainty in the estimates of effect size for pain reduction compared to placebo in patients with knee osteoarthritis followed for at least 12 months [12].

Polydeoxyribonucleotide (PDRN) consists of polymers with deoxyribonucleotides of various lengths, extracted from trout or salmon sperm [3]. These polynucleotides have the significant water-binding capacity, potentially restructuring cartilage surfaces by organizing and regulating water molecules within a three-dimensional gel. When administered into a joint, they offer deep hydration to the joint surface [4]. In a study by Gennero et al., chondrocytes exposed to PDRN exhibited improved cell viability compared to cells treated with HA. Furthermore, PDRN-treated cells showed reduced proteoglycan degradation, which is a key component of the cartilage extracellular matrix [5]. The researchers concluded that PDRN’s ability to safeguard cartilage may make it a more effective treatment option than HA [5,13,14].

One randomized controlled trial compared the efficacy and safety of intra-articular injections of PDRN and HA, reporting that there were no significant differences between intra-articular PDRN injections and HA injections in terms of both efficacy and safety [6]. According to the results of a Systematic Review and Meta-Analysis, intra-articular PDRN injections may serve as a promising alternative to HA injections for treating persistent pain associated with OA, while potentially avoiding side effects [15]. Moreover, unlike NSAIDs, PDRN exhibits anti-inflammatory effects without metabolic side effects, indicating its potential as a steroid replacement in the treatment of musculoskeletal diseases [16].

There has been little information revealed so far regarding complications associated with PDRN injections. In our case, we reported the diagnosis, treatment, and prognosis of pseudoseptic arthritis that developed after an intra-articular PDRN injection.

Pseudoseptic arthritis presents as an acute inflammatory monoarthritis that closely resembles the clinical signs of septic arthritis. Symptoms such as pain, swelling, joint effusion, fever, erythema, and warmth are similar to those seen in septic arthritis [10]. Typically, these symptoms manifest within 72 hours following an intra-articular injection. The key factor differentiating pseudoseptic arthritis from septic arthritis is the absence of microorganisms in the synovial fluid.

One distinguishing factor between septic arthritis and pseudoseptic arthritis is the WBC count in the synovial fluid. Generally, a WBC count exceeding 50,000/mm³ is considered the threshold for diagnosing septic arthritis [17]. In this case, despite presenting with clinical features resembling septic arthritis, the synovial fluid gram stain was negative, and the WBC count was below 50,000/mm³, which did not meet the diagnostic criteria for septic arthritis.

Pseudoseptic arthritis also needs to be differentiated from autoimmune inflammatory arthritis or microcrystalline inflammatory arthritis [18]. However, in this case, the patient had no history of autoimmune diseases. Furthermore, the synovial fluid's crystal analysis came back negative, ruling out crystal-induced arthritis.

Pseudoseptic arthritis can often be mistaken for infectious arthritis, and as a result, surgical treatment may sometimes be necessary to address the condition, particularly when initial clinical findings strongly suggest an infection [18,19]. In our case, the patient presented to the emergency department with symptoms closely resembling septic arthritis, leading to admission and surgery the following day. The final diagnosis of pseudoseptic arthritis was established through culture results from the surgical specimen.

Pseudoseptic arthritis is a very rare complication. To date, the primary cause of pseudoseptic arthritis related to intra-articular injections has been associated with HA [9]. The characteristics of pseudoseptic arthritis caused by HA are as follows: (1) severe joint effusion accompanied by intense pain occurring within 24 to 72 hours post-injection; (2) the necessity of two or three injections before the onset of immune sensitization; (3) absence of infectious agents and calcium pyrophosphate crystals in aspirated synovial fluid; (4) possible elevation of mononuclear cell levels in synovial fluid (predominantly macrophages, occasional neutrophils, and increased eosinophils); and (5) a disease course that rarely resolves spontaneously and usually requires treatment, such as joint aspiration, intra-articular corticosteroid injection, or NSAIDs [17].

In comparison with HA, the following observations were made in our case of PDRN-related pseudoseptic arthritis: (1) the symptoms appeared one week after the injection; (2) there was a prior injection one month earlier; (3) no infectious agents or crystals were found in the synovial fluid aspirate; (4) no significant elevation of mononuclear cell levels in the synovial fluid was observed; and (5) the disease did not resolve spontaneously. While some features resemble those of HA-induced pseudoseptic arthritis, others differ.

To the best of our knowledge, there have been no reports of pseudoseptic arthritis associated with PDRN intra-articular injections. Currently, HA is considered the primary cause of pseudoseptic arthritis following intra-articular injections, and various studies have been published on this topic [9]. A recent case report described the occurrence of pseudoseptic arthritis following an intra-articular injection of platelet-rich plasma [10]. In our case, pseudoseptic arthritis developed after an intra-articular injection of PDRN. This suggests that the possibility of pseudoseptic arthritis should be considered not only with HA but also with other agents used for intra-articular injections.

This report was approved by the Institutional Review Board (IRB) of the Seoul National University Hospital (Seoul, Republic of Korea) (IRB no. 2411-007-1581).

No potential conflict of interest relevant to this article was reported.