The role of synovectomy in the management of a target joint
The authors stated that they had no interests which might be perceived as posing a conflict or bias.
What is synovitis?
The primary goal of individuals who provide musculoskeletal care of persons with haemophilia must be ensure that our patients reach adulthood without compromise of osteoarticular performance. In order to achieve this objective, the number of bleeds occurring in the musculoskeletal system must be kept to a minimum to prevent the permanent inflammation of the synovial tissue known as chronic synovitis. When activated, the synovial tissue appears to play a central role in the development of arthropathy in patients with haemophilia through various mechanisms [1,2].
Why is synovitis deleterious to the joint?
Repetitive haemorrhages to the joint produces large deposits of iron. Iron induces genes involved in cellular proliferation and stimulation of inflammatory cytokines. In vitro studies evaluating the effect of iron on human synovial tissue demonstrate a dose-dependent increase in the expression of the proto-oncogene c-myc and synovial proliferation [3]. Iron induces expression of mdm2, a p53 tumour suppressor binding protein. In addition to its effect on synovial proliferation, iron deposition also contributes to articular cartilage destruction, through stimulating the inflammatory cytokines interleukin-6, interleukin-1, and tumour necrosis factor [3].
Both in vivo and in vitro studies suggest blood may exert a more direct toxic effect on articular cartilage. In vitro studies reveal a marked inhibition of proteoglycan synthesis by whole blood [4]. Canine experiments demonstrate that exposure of the cartilage to blood results in biochemical and histochemical changes in the cartilage matrix and chondrocyte metabolic activity. Furthermore, these animal studies suggest that the articular cartilage of young animals is more susceptible to these changes than that of older animals [5].
The macrophage infiltrate seen in human haemophilic synovial tissue was co-localized with secreted pro-angiogenic factors, including vascular endothelial growth factor, basic fibroblastic growth factor, matrix metalloproteinase-9, tumour necrosis factor-a and cyclooxygenase-2. Additionally, haemophiliacs with joint disease exhibited a fivefold increase in 12 circulating angiogenesis-related cytokines compared with individuals with a bleeding disorder without joint disease and compared with healthy control subjects as profiled by a protein array. Plasma vascular endothelial growth factor and matrix metalloproteinase-9 are significantly elevated in haemophiliacs with joint disease compared with those without joint disease (P = 0.001 and 0.029, respectively). It is now clear that the intra-articular presence of blood is transduced into angiogenesis, the release of inflammatory cytokines, and proto-oncogene expression, all known to be deleterious to cartilage, bone and ligaments [6]. The co-existence of proto-oncogene expression, angiogenesis and inflammatory cytokines in response to repetitive bleeding into a joint can result in infiltration and propagation of the synovium and lead to joint destruction.
How long can chronic synovitis go on without damaging the joint?
On the average, the latency between the initiation of musculoskeletal bleeds and appropriate intervention is longer that ideal. There is enough evidence to support the concept that secondary prophylaxis limits but does not abolish the progression of bleed-related arthropathy [7]. Additionally, incremental joint damage seems to take place with delays in the initiation of treatment. Fisher et al. demonstrated that an incremental deterioration of 8% (95% CI 1–16%) in the Petterson score was observed in children for every year the initiation of prophylaxis was delayed after the first joint bleed [8]. The authors conclude that the longer the start of prophylaxis is postponed after the first joint bleed, the higher the risk of developing arthropathy [8]. For a number of years, it was assumed that in the absence of a target joint or clinically detectable synovitis, persons with haemophilia were safe in terms of undergoing articular deterioration [9]. Manco-Johnson et al. did away with this paradigm in a randomized controlled trial in which they assigned young boys with severe haemophilia A to regular infusions of recombinant factor VIII (FVIII) (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totalling a minimum of 80 IU of FVIII per kilogram of body weight at the time of a joint haemorrhage [10]. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees and elbows) by radiography or magnetic resonance imaging (MRI). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P = 0.006). The authors were puzzled by the fact that the number of clinically evident haemarthrosis correlated weakly with the outcome as determined by MRI. In addition, joint abnormalities were not apparent on physical examination in the very young children in their study. A groundbreaking observation in this study is that the absence of overt haemarthroses and abnormalities of joints on physical examination can lead to the erroneous assumption that episodic therapy in young children with haemophilia is effective. Therefore, the authors propose that chronic micro haemorrhage into the joints or subchondral bone in young boys with haemophilia causes deterioration of joints without clinical evidence of haemarthroses and that prophylaxis prevents this subclinical process [9]. There is evidence to conclude that joint damage is underway even before synovitis becomes clinically detectable. Therefore, besides primary prophylaxis, the key to the successful prevention of degenerative arthritis remains the management of initial haemarthrosis, before the development of chronic synovitis and articular surface erosions [10].
Treatment of synovitis
Persons with haemophilia with chronic synovitis are a heterogeneous group. The degree of severity of synovitis and its resistance to treatment will be the result of a combination of variables, for example, the degree of severity of haemophilia, association of haemophilia with other coagulopathies, presence of inhibitors, age at which the initial articular symptoms develop and at which treatment is started and the frequency with which the bleeds occur (phenotype). Furthermore, a patient will require treatment for synovitis that is refractory to medical treatment in one of three circumstances: (i) synovitis that developed while on primary prophylaxis; (ii) synovitis developed without prophylaxis that did not respond to treatment with secondary prophylaxis; or (iii) synovitis developed in the absence of access to primary or secondary prophylaxis. It is likely that the prognosis in each of the three distinct treatment groups would be different; however, we ignore this and address them collectively. Additional complexity results from the fact that most of the knowledge on the treatment of synovitis is derived from Grade IV evidence, typically obtained from case series or at best, cohort studies. Therefore, our current treatment guidelines result from a combination of consensus from experts and feedback from patients, families and National Member Organizations.
Types of synovectomies
A number of interdisciplinary strategies must precede invasive synovectomies and are required for the success of treatment even in the presence of the percutaneous procedures [10,11]. The discussion of these valuable procedures is beyond the scope of this paper. Invasive treatment of synovitis is staged in three levels of complexity:
- 1
The first step in treatment is to attempt inactivation of the synovium with substances injected percutaneously [12]. There is a strong trend towards agreement that radioisotopes (yttrium, disprosium, rhenium or phosporus) achieve this goal quicker and more reliably than chemical agents (rifampin or oxytetracycline) [12,13]. Considerations, such as regional availability, cost, complexity of the institution and accessibility of the treatment centre for persons with haemophilia will influence the choice of methodology and therapeutic agent. Up to three applications of radioisotope (three-month intervals) and up to seven of chemical agents (at weekly intervals) with incremental clinical response are appropriate before considering moving on to the next level of invasiveness [13–21].
- 2
Arthroscopic synovectomy is recognized as an effective method of synovial deactivation. While its use as a first option has some advantages, there is general consensus that it is best used as a second level of defence. The procedure requires surgical expertise and meticulous execution, and allows access to the vast majority of the joint with minimal external incisions. Patients require hospitalization, surgical amounts of clotting factor replacement and dedicated physiotherapy [22]. The technique allows removal of osteophytes, treatment of chondral lesions and remodelling of meniscal tears, which are characteristic of Grade III and IV arthropathy [23]. On rare occasions upon failure of arthroscopy and when confronted with the need to perform posterior releases of the joint or osteotomies to correct flexion deformities, one may need to progress to the third level of invasiveness.
- 3
Open synovectomy. The success rate of open synovectomy in controlling recurrent bleeding is over 80%. However, open synovectomies have a lengthy post-operative course and require surgical amounts of concentrate for prolonged periods since they are remarkably difficult to rehabilitate. In order to have access to the entire synovial surface, a minimum of two incisions are required, thus contributing to the difficulty in regaining range of motion. For these reasons, open synovectomies have fallen in disrepute [24].
Summary
Synovitis is a destructive state for the joint, in which assertive treatment should be instituted immediately after diagnosis. Current understanding of synovitis and its immediate and often irreversible repercussions on the wellbeing of the joint suggest that no latency between its initiation and treatment is appropriate [8]. Synovitis is a call for action. The objectives of treatment are: to de-activate the synovium immediately, returning the joint to a state where physiotherapy may work towards complete range of motion, muscle strength and joint speed, and prophylaxis is effective in preventing articular bleeds [9]. Achieving the goal of reaching adulthood without compromise of osteoarticular performance requires immediate treatment of synovitis to prevent irreversible joint deterioration and increased cost [25,26]. It must be a central objective of education for WFH to enable patient’s relatives and healthcare workers to recognize chronic synovitis as a severe condition requiring immediate treatment.
