Ozone therapy for the treatment of recurrent pigmented villonodular synovitis of the knee.

Dear Editor,

Pigmented villonodular synovitis (PVNS) is a benign proliferative condition that develops in the synovial membranes of joints, bursa or tendon sheaths most frequently in the knee joints. The patient usually has mono-articular pain and swelling. Aspiration of the joint characteristically reveals blood-tinged fluid. The synovial tissue has a characteristic brownish discoloration due to hemosiderin deposits. As the condition reaches an advanced stage, erosive lesions can be detected in the adjacent bony structures. As the weight-bearing extremities are most prone to this, the knee joint (70%) is particularly affected, although there can be involvement of the ankle, shoulder, wrist, and other joints. Patients usually complain of progressive joint swelling and discomfort with insidious onset. PVNS can occur in all age groups, but those aged 20–50 years are the most frequently affected.1

Plain radiographs usually show non-specific features such as bony erosions or soft tissue swelling. Computed tomography and ultrasonography can also show the hypertrophic synovium as a slightly hyper dense/echogenic soft-tissue mass. In the differentiation of PVNS from other synovial diseases, magnetic resonance imaging is of benefit as hyperplastic synovium or localized mass lesions are indicated by an abnormally low signal intensity on both T1 and T2 weighed images. Magnetic resonance imaging has the advantages of showing mass-like synovial proliferation with lobulated margins, with low signal intensity and hemosiderin deposits seen as “blooming” artifact on gradient echo.2 Here, the case is described of a patient with a history of knee pain and swelling, who was diagnosed with localized PVNS, and was treated successfully with local ozone therapy. This is the first case which describes treatment with ozone of PVNS in a patient refractory to surgical treatment. A 30-year old female presented with complaints of pain and swelling in the left knee which had been ongoing for 3 years. Initial assessment of pain was 7 on the Numeric Rating Scale. The patient had a history of arthroscopic synoviectomy 10 years previously because of PVNS and the pain was relieved after surgery. On examination, the range of motion of the knee joint was limited to 120° of active flexion, with full extension. Laboratory test results showed: C-reactive protein = 2 mg/L (normal range: 0–5 mg/L), erythrocyte sedimentation rate = 15 mm/h (normal range: 0–20 mm/h), rheumatoid factor = 9 IU/mL (normal range: 0–20 IU/mL), anti-cyclic citrullinated peptide = 0.5 U/mL (normal range: 0–20 U/mL). In addition, complete blood count, hepatic panel, blood urea nitrogen and creatinine levels were within normal limits. Radiographs were normal. Magnetic resonance imaging showed a 22 mm × 12 mm hypodense nodular lesion around the posterior longitudinal ligament (). PVNS was diagnosed based on these findings. The patient was treated with arthroscopic plica excision and synoviectomy. Two months after surgery, the symptoms had not decreased. A total of 15 sessions of intra-articular injections of 15 mL local ozone (O2-O3mixture) were applied to the patient (). The first five sessions were applied at 3-day intervals at a dosage of 15 µg/mL, and the subsequent five sessions at 20 µg/mL. The final five sessions were applied at 10-day intervals at dosages of 20, 30, 40, 50, and 60 µg/mL. The pain gradually relieved and at the end of 3 months the Numeric Rating Scale was 0. The patient has not suffered even mild knee pain since January 2020 to date.

A case of ozone therapy for recurrent pigmented villonodular synovitis of the knee.

Note: A 30-year old female was diagnosed with localized pigmented villonodular synovitis. (A) Magnetic resonance imaging image showing a 22 mm × 12 mm hypodense nodular lesion around the posterior longitudinal ligament (arrows) and suprapatellar effusion. (B) Intra-articular ozone injection into the knee joint.

There are two types of PVNS: the localized form affects just one area of the joint or only the tendons that support the joint. The diffuse form, which is seen more frequently (80%) involves the whole joint lining, and can be more difficult to treat than local PVNS. Recurrence is a reported problem with the diffuse form of PVNS, whereas only a few cases of recurrence of the local variety have been reported.3 PVNS treatment depends on the degree of injury in the joint and patient age. The most favorable treatment modality of PVNS is surgical removal of all pathological tissue. This can be applied by open or arthroscopic methods. Local recurrence after treatment has been reported in 18–46% of patients. In the event of residual or recurrent disease, other treatment modalities can be applied, such as radiotherapy, radiation synovectomy, cryosurgery, total joint arthroplasty and immune or targeted therapy.4

Ozone therapy in Turkey is regulated by the “Regulation of Traditional and Complementary Medicine Practice” issued by the Ministry of Health in the Official Gazette of the Republic of Turkey.5 Ozone therapy can be used as a supportive therapeutic method for various diseases including soft tissue injuries, osteoarthritis, rheumatologic diseases, referred pain associated with vertebrae and disc pathologies (paravertebral or intradiscal injections), myofascial pain syndrome, fibromyalgia syndrome, diabetic wounds, gingivitis, periodontitis, neuropathic pain, infected diabetic wounds, extremity wounds with critical ischemia for which revascularization is not practicable.5

In the treatment of inflammatory diseases related to the musculoskeletal system, there has been an increase in recent years in the use of ozone injections, which activate the anti-inflammatory and anti-oxidative capacity. Ozone therapy has shown that ozone can be safely used at doses between 10 and 80 µg/mL, with immunomodulatory, anti-inflammatory, bactericidal, antifungal and analgesic effects at these doses. Treatment with ozone can improve tissue oxygenation and inhibit inflammatory mediators via down-regulation of the pro-inflammatory cytokines such as prostaglandin E2, phospholipase A2, cyclooxygenase I–II, callicrein and bradykinin. Ozone therapy can also induce moderate-intensity oxidative stress and inhibit local inflammatory responses.6

It has been reported that the anti-nociceptive effect of ozone occurs through a series of mechanisms. Through direct stimulation of the transient receptor potential A1, which is associated with inflammatory factors, a subset of C-fibers are activated by ozone. Following exposure to ozone, nerve growth factor is inhibited, which may reduce the ozone-induced substance-P response, and when interleukin-1β is suppressed, the release of both nerve growth factor and substance-P can be attenuated. The direct mechanism of pain relief by ozone is thought to be the inhibition of the inflammatory response. As a result of these factors relieving pain, knee function also improves.3,4

As there are few therapeutic options and local recurrence may occur at rates of up to 50%, local ozone injections have been suggested as a therapeutic option in PVNS. With the use of ozone injections, there are no side-effects such as vessel-nerve damage and skin ulceration, which may occur in surgery or radiotherapy. In addition, there are no joint problems associated with immobilization and a long healing period after surgery.

The authors certify that they have obtained the appropriate written consent form from the patient.