Abstract: Erosive osteoarthritis (EOA) represents a subset of symptomatic osteoarthritis of hand, characterized by intermittent and often frequent inflammatory episodes and progressive joint damage. A greater degree of inflammation and the presence of subchondral bone erosions on plain radiographs help distinguish EOA from generalized osteoarthritis of hand. High resolution ultrasound and magnetic resonance imaging (MRI) have demonstrated the presence of synovitis and MRI has additionally highlighted the role of inflammation in bone, tendons, and ligaments in EOA. Further evidence for the crucial role of inflammation comes from recent studies that have unraveled the roles for several cytokines in the pathogenesis of EOA. Despite these advances, treatment options for EOA to date have been of modest benefit. Additional research is therefore needed to better understand the pathogenesis of EOA and lead to the development of novel therapeutic agents for this disabling form of arthritis.
Erosive osteoarthritis (EOA) is a form of osteoarthritis (OA) marked by a greater degree of inflammation and characterized by the presence of erosions on plain radiographs. The classic clinical description is of OA that affects the distal interphalangeal (DIP) and proximal interphalangeal (PIP), often associated with synovitis and cyst formation. While initial descriptions of EOA may have been made by Kellgren and Moore (1952), the term erosive osteoarthritis was first coined by Peter et al. (1966) in 1966. Others have used the term inflammatory OA to describe the same subset of patients (Ehrlich, 1972). While EOA is considered to be a variant of OA by most, controversy remains as to whether it is a distinct entity or a phase of nodal OA.
OA of hand is estimated to affect 70% of those over age 65 (Hochberg, 1991; Van Saase et al., 1989). EOA is thought to be a relatively uncommon clinical subset with an estimated prevalence of 5-15% of those with symptomatic hand OA (Ehrlich, 2001). EOA predominantly affects postmenopausal women with a female:male ratio of 12:1 (Greenspan, 2003). In our cohort of 70 subjects, 80% were female (Anandarajah et al., 2009). Other studies have described as many as 91.6% of affected subjects being women (Punzi et al., 2004). The typical age of onset appears to be between 50-55 years (Greenspan, 2003; Punzi et al., 2004).
The absence of established diagnostic criteria or a validated case definition for EOA is an obstacle to scientific research in EOA. For the purpose of our studies we have defined EOA as OA of hands based on the American College of Rheumatology (ACR) criteria (Altamn et al., 1990), along with the presence of erosions in at least 2 DIP joints on plain radiographs, in patients with a negative rheumatoid factor and/or anti-cyclic citrullinated peptide antibody, absence of personal and family history for psoriatic arthritis (PsA), and negative history for crystal induced arthropathies. An emphasis on the presence of central erosions on plain films and normal or near normal acute phase reactants (sedimentation rate and wide range C-reactive protein) may add to the specificity of the proposed criteria shown in Table 1.
|Table 1. Proposed Diagnostic Criteria for Erosive Osteoarthritis|
|• OA of hands based on the American College of Rheumatology|
|• Erosions in at least 2 interphalangeal joints of which one must be a DIP joint|
|• Negative rheumatoid factor and/or negative anti-citrullinated protein/peptide antibody|
|• Absence of personal and family history for psoriatic arthritis|
|• Absence of history of Gout and Chondrocalcinosis affecting hands|
|º Presence of central subchondral erosions|
|º Normal (or near normal) erythrocyte sedimentation rate (ESR)|
|º Normal (or near normal) wide range C-reactive protein|
|Note: The first 2 points are essential for diagnosis of EOA. The 3 points preceded by a white circle
will add to specificity of diagnosis.
Pain, swelling and warmth of the DIP and PIP joints are the most common symptoms. Pain is often of abrupt onset and is followed in most cases by intermittent inflammatory episodes with progressive joint destruction (Anandarajah et al., 2009). EOA is associated with morning stiffness that could last up to an hour. Throbbing paresthesia is described as a characteristic feature (Belhorn and Hess, 1993). While presentation is typically bilateral and symmetrical, DIP joints are more frequently affected than the PIP joints. The second and third DIP joints are most frequently involved followed by the fourth and fifth DIP joints (Punzi et al., 2004). Although the feet may be less frequently affected than hands, our studies suggest that it may be more common than initially described (Anandarajah et al., 2009). Indeed, other studies have also reported on foot involvement (Ehrlich, 1972; McKendry, 1985; Mas and Rotes-Querol, 2007). Large joint involvement is recognized but presumed to be rare (Ehrlich, 1972; Keats et al., 1981). Exam often reveals tenderness and the presence of Heberden’s and Bouchard’s nodes. Deformities in the form of subluxations, flexion contractures, and ankylosis may also be seen. Progression of deformities often leads to impaired hand function.
Pain and loss of hand function are known to negatively impact patients with hand OA and contribute to a decrease in quality of life measures (Slatkowsky-Christensen et al., 2007). Hand function has shown to be even more compromised in EOA compared to patients with nodal OA who do not have erosions. Patrick et al. (1989) reported on a study of hand function in 59 patients with nodal generalized OA (NGOA) compared with 10 subjects with EOA and 52 healthy controls, matched for age and sex. Hand function was assessed by standardized tests to evaluate mechanical function and radiographs scored for joint space narrowing, osteophyte, sclerosis, and cystic lesions. Pain and difficulty performing tasks were most common in patients with EOA and least common in controls. Patients with EOA also took significantly longer than controls and patients with NGOA to complete assigned tasks. Additionally, total radiographic scores were significantly higher in patients with EOA than NGOA patients and scores in both NGOA and EOA groups were significantly higher than in controls. It should be noted that patients with EOA had a longer disease duration. This study, however, supports the notion that patients with EOA have more pain, worse hand function, and more severe radiographic damage than those with nodal OA of hands.
EOA is characterized by the presence of erosions often in combination with bony proliferation that can vary in extent. Classical radiographic findings include those of central erosions, collapse of the subchondral bone, and interosseous bone fusion (Ehrlich, 1972; McKendry, 1985). Joint space narrowing and subchondral sclerosis are often seen in conjunction with above findings. The central erosion and marginal osteophytosis often lead to the hallmark “gull-wing” deformity (Martel et al., 1980) (Figure 1a). Another type of lesion, the saw tooth erosion (Figure 1a), often eventually leads to ankylosis (Greenspan, 2003). Additionally, telescoping or opera glass deformity has been described (Greenspan, 2003; Swezey and Alexander, 1971). Ankylosis is estimated to occur in about 15% of patients with EOA. Soft tissue swelling and effusions have also been described (Punzi, 2004). In our cohort, based on criteria described in Table 1, we found joint space narrowing to be the most common finding seen in 98%, followed by osteophyte formation (Figure 1b) (96%), subchondral sclerosis (88%), and ankylosis (21%) (Figure 2). The classic radiographic lesions of EOA are seen at the DIP and PIP joints. Erosions have also been described in feet (Figure 1c), knees, hips, shoulders, and spine (Belhorn and Hess, 1993; Keats, 1981; Swezey and Alexander, 1971; Utsinger et al., 1978).
Findings on Ultrasound
High frequency ultrasound is widely accepted as a more sensitive technique than radiographs in detecting bone erosions and provides the advantage of identifying soft tissue changes, in assessment of musculoskeletal diseases (Grassi et al., 2001). The development of very high frequency transducers has made the examination of small joints possible, without the loss of resolution. In a study of DIP joints, Grassi et al. (2000) demonstrated that ultrasound allowed for visualization of the joint, extensor and flexor tendons, bone margins, periarticular and peritendinous soft tissues, and blood vessels. Furthermore, this pilot study reported the presence of osteophytes, synovitis, and changes in bone margins of patients with EOA.
An Italian study evaluated the role of high resolution ultrasound in the detection of bone erosions in EOA (Iagnocco et al., 2005). Twenty two patients with EOA, based on the presence of central erosions, subchondral plate collapse, and bone ankylosis with a mean duration of 3.9 years from onset of symptoms were compared with 88 patients with classical OA without erosions. Longitudinal and transverse ultrasound scans were performed on both volar and dorsal sides of all DIP and PIP joints of both hands. Erosion was defined as a cortical break seen in longitudinal and transverse scans (Grassi et al., 2000). Central erosions were detected in 16 of 22 patients (73%) with erosive OA and in none of the patients with classical OA. The authors concluded that the interposition of osteophytes may have limited the ability to identify the erosions in the other 27.3%.
A recent study addressed the presence of inflammatory changes on sonographic findings in EOA patients (Vlychou et al., 2009). The study compared the findings on ultrasound with radiographic findings in 22 patients with EOA. Ultrasound examinations of all MCP, IP, and CMC joints (30 joints per subject) were performed on the 22 patients (total of 660 joint examinations) for central joint erosions, osteophytes, joint effusion, synovitis, tenosynovitis, and power Doppler findings. Ultrasound and radiographic findings were recorded as present or absent. Detection of erosions and osteophytes was significantly more frequent on ultrasound compared to radiographs. Ultrasound also detected the presence of thickened synovium in 24% of joints (19 of 22 patients) and power Doppler signals were noted in 22% of joints (18 of 22 patients). Effusion and tenosynovitis were also noted in some subjects. This study shows that ultrasound is more sensitive than radiographs in detecting erosions in EOA. Taken together these studies suggest that the use of ultrasound might help detect erosions early and additionally provide valuable information on the presence of synovitis and inflammatory changes in other soft tissues. In addition to providing clues to the pathogenesis of EOA the findings on ultrasound may also help in the assessment of therapeutic agents in the treatment of EOA.
Tan et al. (2005) compared findings on high resolution MRI of PIP or DIP joints in 16 patients with early OA (symptom duration of less than 12 months), 14 with chronic OA (duration of more than 12 months), 10 OA patients with asymptomatic joints, and 18 healthy controls. Erosions were detected in 11 patients with early OA, 7 of those with chronic OA, and in one of the asymptomatic joints of OA patients. No erosions were observed in healthy controls. Joint inflammation as determined by gadolinium uptake was frequently seen in the synovium, ligaments, tendons, and bone marrow of patients with acute and chronic OA. The study did not include plain radiographs and therefore it is unclear whether the patients with erosions on MRI fulfilled criteria for diagnosis of EOA.
Another study by the same authors reported that erosions are a common finding on high resolution MRI in patients with hand OA (Grainger et al., 2007). This study enrolled 15 patients with OA of hands based on the ACR criteria (Altman et al., 1990). One affected DIP or PIP joint was selected for MR imaging (1.5 Tesla) regardless of findings on radiographs. The Outcome Measured in Rheumatoid Arthritis Clinical Trials (OMERACT) definition for erosions in RA was used to analyze MRI (Ostergaard et al., 2003). Erosions were further classified as central when occurring in the subchondral bone or marginal when seen at the edge of the articular surface. Six of 15 subjects (40%) were noted to have erosions on radiographs with central erosions present in all 6, and one subject also with marginal erosion. On MRI, 12 of 15 (80%) subjects had erosions with marginal erosions noted in all 12. Marginal erosions were associated with the presence of bone marrow edema in 89% and hypertrophied synovium in all cases. Adjacent areas of marrow edema were seen in only 50% of central erosions. These findings suggest that the pathology of marginal erosions may be different from that of central erosions. Furthermore, the relatively high prevalence of erosions on MRI in subjects with hand OA raises the possibility that EOA is more common than previously reported. These studies provide evidence for inflammatory changes in hand OA and thereby provide further clues to its pathogenesis. However, there are to date no studies that have examined the utility of MRI exclusively in patients with EOA.
Over the past decade, several studies have emphasized the roles of synovium, bone, and ligaments in addition to cartilage in the pathogenesis of OA, which supports the current paradigm that OA is a disease of the entire joint. Genetic, biochemical, and biomechanical factors with variable degree of inflammation are likewise speculated to contribute to the pathogenesis of EOA.
Excessive cartilage destruction, a key finding in OA, is secondary to a loss of equilibrium between cartilage formation and degradation. Evidence for increased cartilage breakdown in EOA has emerged from studies that have demonstrated an increased serum levels of cartilage metabolism markers in EOA compared to healthy controls (Silvestri et al., 2004). The loss of cartilage is orchestrated by chondrocytes which in turn respond to mechanical stimuli, joint instability due to genetic factors, and biological stimuli from several cytokines and proteinases. Synovial inflammation is increasingly recognized as playing a crucial role in the etiology of pain in OA and may also be a source of the inflammatory cytokines (Benito et al., 2005; Bondeson et al., 2010; Hill et al., 2007). The presence of synovitis in EOA has been highlighted over the years. Peter et al. (1966) described the presence of proliferative synovitis during the inflammatory phase of the disease. Another study by Goldie et al. (1973) noted chronic inflammatory changes in synovial tissue from the DIP joint in 5 patients. Belhorn et al. (1993) described that synovial fluid analysis may point to a mild inflammatory arthritis. Somewhat surprisingly no histological studies have been published in the past 3 decades. However, the advances in ultrasound and MRI technology have allowed for the assessment of synovitis in joints of patients with EOA (Figure 1d) (Vlychou et al., 2009; Tan et al., 2005; Grainger et al., 2007). Osteophyte formation and bone sclerosis point to involvement of bone in EOA while the role of ligaments is highlighted by studies that show damage to collateral ligaments preceding joint disease in patients with OA of hands (Tan et al., 2005).
The role of inflammatory cytokines in the pathophysiology of EOA is not yet fully understood, but indirect evidence has emerged over the past few years. Studies have demonstrated high serum levels of interleukin-2 (IL-2) in patients with EOA compared with patients with hand OA without erosions (Punzi et al., 1996). Other studies have noted an association between EOA and a genomic region containing the interleukin-1 beta 5810 single nucleotide polymorphism (IL-1B 5810 SNP) in a U.S. Caucasoid population (Stern et al., 2003). Silvestri et al. (2006) demonstrated an increase in serum levels of IL-4 receptors (sIL-R4) in patients with EOA as well as in patients with nodal OA of hands and knee and hip OA compared with healthy controls. IL-4 mediates an anti-inflammatory effect by down-regulating effects of IL-1 and tumor necrosis factor-α (TNF-α). An increase in sIL-4R may therefore be associated with a decrease in availability of IL-4, thereby contributing to the initiation of joint damage in EOA. Adipose tissue has been proposed to be a major source of inflammatory cytokines. Adiponectin, a protein hormone secreted by adipose tissue, regulates metabolism of lipids and glucose and additionally has been demonstrated to be involved in inflammatory process in destructive arthritides (Ehling et al., 2006). Interestingly, a recent report showed that serum adiponectin levels were elevated in EOA patients compared with non-erosive OA and healthy controls matched for age and body mass index (Filkova et al., 2009). This finding further supports the association between obesity and OA of small joints (Cicuttini et al., 1996).
OA of hands, especially when associated with Heberden’s and Bouchard’s nodes, is known to have a genetic basis (Stecher and Hersh, 1944; Kellgren et al., 1963). Although, a tendency to familial aggregation has also been described in EOA, few trials have investigated the role of genetics in EOA. Peter et al. (1966) noted an increase in MZ α1-antitrypsin phenotype in patients with EOA compared with standard reference population. Punzi et al. (2004) also reported a study that detected a higher frequency of DRB1*011 antigen in EOA in comparison with nodal OA.
As with OA, treatment of EOA is often restricted to controlling symptoms. Non-pharmacologic therapy in the form of moist heat, paraffin baths, splinting, and range of motion exercises are often utilized by physical and occupational therapists. Although, initial therapy is often with acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), use of these medications may be prohibitive in the elderly patients. Furthermore, these therapies often only provide modest control of symptoms. Intra-articular injections have been reported to be of benefit in some EOA patients (Utsinger et al., 1978). Our experience suggests that intra-articular steroids provide temporary relief, but injections of small joints are often painful and do not prevent progression of erosions. Several trials of chondroitin sulphate in EOA reported decreased pain and inhibition of radiographic progression of erosions, but most studies comprised small numbers of subjects and were not randomized, placebo-controlled trials (Rovetta et al., 2002; Rovetta et al., 2004; Verbruggen, 2006). Verbruggen et al. (1998) conducted a randomized, double-blind, placebo-controlled trial to study the effects of chondroitin in 119 patients with OA of hands. Chondroitin sulfate was given to 34 subjects while the other 85 were on placebo. Radiological progression, over 3 years, was assessed by examining for the presence of joint space narrowing and erosions in the PIP and DIP joints that were not affected at baseline. Erosions were noted in 29.4% of patients on placebo compared with in only 8.8% of patients treated with chondroitin, at the end of 3 years. While an interesting observation, the study did not outline the diagnostic criteria for patients or provide demographic details on patients enrolled in the trial and also did not quantify extent of erosions. The possible mechanism for the effects of chondroitin is beyond the scope of this article but has been reviewed elsewhere (Iovu et al., 2008).
Disease Modifying Anti-Rheumatic Drugs (DMARDs) have also been utilized for the treatment of EOA. Some studies have demonstrated that hydroxychloroquine is well tolerated and may be associated with improvement in markers of inflammation (Bryant et al., 1995; Punzi et al., 1996). The inhibitory effect on lysosomal phospholipase A, IL-1, and IL-2 is proposed to contribute to the beneficial effects of hydroxychloroquine in EOA. While the use of methotrexate and oral gold has been discussed, no published data on clinical trials with these agents are available to date (Belhorn and Hess, 1993). None of these medications has been demonstrated to inhibit radiographic progression in EOA.
The use of biologic therapies for the treatment of inflammatory arthritides has revolutionized the field of rheumatology. Additionally, IL-1 and TNF-α have been shown to play a key role in pathogenesis of OA (Kobayashi et al., 2005). It is therefore no surprise that biologic agents have been investigated for the treatment of EOA. A report of 3 patients with severe EOA treated with Anakinra, noted improvement in pain scale and patient global assessment (Bacconnier et al., 2009). Additionally all patients were able to stop the use of NSAIDs. A pilot study of 10 patients with EOA investigated the role of intra-articular injections of infliximab in PIP and DIP joints in comparison to injections of saline (Fioravanti et al., 2009). At the end of 1 year, all patients treated with infliximab were noted to have a significant decrease in pain and tenderness. Interestingly, a decrease in the radiological score was also noted but did not reach statistical significance. A recent pilot trial investigated the role of anti-TNF therapy for the treatment of EOA (Magnano et al., 2007). In this open label trial, 12 patients with moderate to severe EOA, defined as the presence of 2 or more tender and 2 or more swollen joints, were given adalimumab 40 mg every other week for 12 weeks. All patients satisfied the ACR criteria for OA and had one or more erosions at the PIP or DIP joint. The primary outcome measures, a 20% improvement in American College of Rheumatology scores (ACR 20) and safety at 12 weeks, were achieved by only one patient. An ACR 20 response is defined as a ≥ 20% improvement in tender and swollen joint counts and ≥ 20% in at least 3 of the following five ACR score set measures: pain, patient global assessment, physician global assessment, self-assessed physical disability, and acute phase reactants (Felson et al., 1995). A significant improvement was noted in the number of swollen joints but no improvement was detected in other measures. All patients tolerated the medication well and no patients required hospitalization during the study. While the result was disappointing, several factors may have influenced the results including the short duration of therapy, the fact that all patients had a long duration of disease, and possible lack of sensitivity of outcome measures used to assess hand function.
EOA, often considered to be a subset of nodal hand OA or to represent one end of the spectrum of OA, is characterized by a more aggressive disease course with consequent increase in pain and decrease in hand function. Imaging studies show a notable inflammatory component, prominent subchondral erosive change, and tendency to instability and ankylosis. Inflammation has been proposed to play an important role in the pathogenesis of EOA. Indeed, early in the disease course the differential diagnosis from other inflammatory arthritides can be difficult, leading to speculation that EOA may be the interface between osteoarthritis and chronic inflammatory polyarthritides. A prospective study is, however, required to show whether IP joint changes reflect an anomaly of the inherent repair process of synovial joints or are secondary to disruption of normal bone remodeling. The absence of classification criteria and the difficulty in identifying patients with early disease have been major impediments to scientific progress in the field. The lack of therapeutic choices especially disease modifying therapies has been a source of frustration for patients and clinicians alike. Future studies that explain the mechanism for bone and cartilage loss, will be necessary to unravel the inflammatory pathways and hopefully can lead to the development of novel therapies for this disabling condition.
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[Discovery Medicine, 9(48):468-477, May 2010.]