Monoarticular juvenile idiopathic arthritis as a distinct clinical entity A proof-of-concept study

Although patients with monoarticular course JIA are currently considered as part of the oligoarticular subtype, they seem to have clinical characteristics somehow different from those with oligoJIA. The present study, with a long-term follow up, seems to confirm this general observation and adds other evidence suggesting that monoJIA may be considered as a separate condition, quite distinct from oligoJIA.

It is well known that oligoJIA has a monoarticular onset in most patients and that lower limbs joints are involved in the majority of them, being the knee the most affected joint (83.9%) followed by ankle (10.2%) and less frequently by other joints (elbow, wrist, and TMJ) [3, 4, 10].

Our study allowed us to evaluate the clinical characteristics of patients in whom from a single joint the disease spread to two or more joints, becoming oligoarticular. This group, defined as “switch”, resulted having the same characteristics as oligoJIA and, compared to monoJIA, had an increased incidence of uveitis, affected more frequently females and was less associated with BJH. Since in our study the switch occurred in 94% of cases within three years of onset, this time interval may represent the time limit for defining a persistent monoJIA.

The comparison between monoJIA with persistent monoarticular course and oligoJIA allowed us to identify the peculiar characteristics of the two groups (Table 1). MonoJIA affects females less frequently than oligoJIA, has a later onset, is less complicated by uveitis but more frequently associated with BJH.

BJH, present in almost two thirds of patients, predominantly affects the lower limbs where the vast majority of monoJIA occurs. These data seem to suggest a possible relevant role of ligament hyperlaxity as a co-causative factor in the pathogenesis of arthritis in monoJIA as compared to oligoJIA, where instead autoimmunity seems to play a major role. In fact, ANA, known markers of autoimmunity, are significantly more frequent in oligo than in monoJIA.

It is well known that BJH is considered a physiological phenomenon in young children [7, 8]. In a previous study, we reported a high prevalence of BJH (63%) among patients with oligoJIA and this frequency was significantly higher than reported by a recent study performed in healthy schoolchildren in the same geographic area (40.5%, p = 0.006) [11, 12]. In the present study, we confirm the high frequency of BJH, particularly in monoJIA. In the literature, subjects with hypermobile joints result having more frequent joint injuries, subluxations, dislocations and other complaints and are more predisposed to arthritis or arthralgia [13‐15]. Indeed, other studies have shown that altered contact mechanics and abnormal articular loading in instable joints may cause increased contact stress directional gradients and articular surface incongruity that may lead to articular cartilage disruption and joint inflammation [16]. Therefore, the mechanical component might be a crucial factor in both triggering for the onset of arthritis and in its persistence.

Interestingly, we found a significantly lower incidence of uveitis in monoJIA both at diagnosis and during the disease course (Table 1). This is another important finding as uveitis is a cause of long-term disability and damage in oligoJIA [5, 17, 18]. We do not have a clear-cut explanation for this. However, it might partially confirm the more ‘local mechanical’ nature of monoJIA, with systemic inflammation playing a minor role. Indeed, the presence of uveitis lead to the early use of DMARDs in the majority of monoJIA patients in our cohort. In fact, 6/9 patients with anterior uveitis (AU) already present at the disease onset had severe disease course and are the same ones who were on bDMARDs treatment at the last evaluation. Furthermore, in most monoJIA patients ocular involvement is present already at diagnosis, it unlikely develops later and in any case in a less severe form.

As far as the outcome is concerned, the results confirm the better outcome of monoJIA, in which the majority of patients (82.2%) were in complete clinical remission at the last evaluation. Conversely, only 44.1% of the oligoJIAs were in complete remission, while the majority (55.9%) were either still active or in remission on DMARDs. These data confirm the results of a large long-term study from Norway in which the 7-year remission rate in a population of 201 patients with oligoJIA was 49.2% [19]. Moreover, our data approximate results from two previous studies in oligoJIA patients observed 10 years after the onset, where CR was reported in only 47% and 45% of cases, respectively [20, 21]. According to a study by Wallace et al. who analyzed 258 patients with oligoJIA, disease remission at 4 years follow up was achieved in 68% of cases with persistent oligoJIA and in only 31% of the extended oligo forms [22].

Among monoJIA, we observed that most patients were in complete remission and among those with AD or CRM, two thirds were on DMARDs for the ocular involvement. These data suggest that the presence of uveitis negatively influences the long-term outcome of monoJIA.

Conversely, among oligoJIA patients, joint involvement remains the major problem in most patients (56%), being arthritis still active, at the last evaluation, in one out of seven.

The fact that monoJIA is a less severe condition was also suggested by the treatment performed during the long-term follow up. In most cases, monoJIA could be managed with IACS that represents the first-line treatment [23‐27]. On the contrary, the need to resort to second level drugs (csDMARD or bDMARD) was significantly higher in oligoJIA (over 80% of cases) as an expression of a more severe and more difficult to treat disease [6, 28].

As for patients with initial single joint onset that evolved towards an oligoarticular course, the most relevant aspect that emerged was that this swithches happens within the first three years since the disease onset. Based on this evidence, we can state that, if a patient has arthritis limited exclusively to one joint for at least three years, the probability that he/she will subsequently evolve towards an oligoarticular involvement is extremely low. On the contrary, it is quite probable this patient will maintain a monoarticular course. This also means that, although monoarticular onset is a fairly frequent occurrence in JIA [29], it is necessary to follow the disease for at least three years before classifying it as monoJIA. Therefore, as a result of this proof-of-concept study, a possible definition of monoJIA should include the following criteria: arthritis of unknown origin with onset before the age of 16 years with involvement of only one joint, after the exclusion of other conditions [30‐33], for a period greater than three years after onset.

Monoarticular JIA has been rarely reported in the literature as isolate condition and mostly as case reports [34, 35] or small case series [36]. In 1965, Bywaters and Ansell, widely considered the founders of pediatric rheumatology in Europe, were the first to describe, within a population of patients with JIA, a homogeneous group of 33 patients with single-joint localization [10]. It is interesting to note how our study, almost 60 years later but with a much larger number of patients and a significantly longer follow-up, reached the same results and conclusions (Table 2). In the latter study fourteen patients had persistent monoJIA course for a follow up period of 3–14 years (mean 6.5), and in 11 (78.6%) the disease was inactive at the last follow-up. Taken together, these data comfort us on the robustness of our observations and confirm that monoJIA may be considered as a distinct clinical entity from oligoJIA.

Defining monoJIA as a new and separate subtype of JIA may foresee a possible change in the therapeutic approach which, in addition to the consolidated IACS treatment, may also include alternative treatment modalities in the most severe or refractory cases, such as arthroscopic synovectomy [37, 38] or radiosynoviorthesis, already used in adult RA [39, 40] and in the pediatric age albeit in different conditions such as emophilia-related arthropathy [41], CACP syndrome [42] or others [43, 44].

A limitation of our study lies in its retrospective nature. However, the study included patients followed with a standardized protocol for many years which allowed the clinical trajectory to be followed in detail.

Strengths are the large patients’ sample considered and their careful classification, the multidisciplinary involvement of rheumatologists and ophthalmologists of the same Center and the limited geographical mobility of the subjects which made it possible to analyze their long-term outcome in real time.