This study failed to demonstrate a role of VBP in CCLR or the presence of a specific pattern of joint inflammation in VBP-positive dogs, even though several canine vector-borne diseases have been associated with joint damage [4, 10, 14, 16,17,18,19,20,21,22, 24], and some of them, especially leishmaniasis, are considered endemic in the area where the present study was performed [28]. Larger case–control studies would likely be needed to clarify the role of various vector-borne organisms as a cause or cofactor in the development of CCLR.

In canine leishmaniasis, the frequency of orthopedic problems had been reported to range from 44.8% to as high as 91.3%, when both orthopedic examination and imaging (radiology and/or computed tomography) were combined to look for joint abnormalities [14, 29]. Some anomalies found in the orthopedic examination include joint stiffness, lameness, soft tissue swelling, joint pain or crepitation, and functional disability. Notably, dogs with CCLR can have one or more of these described orthopedic abnormalities, but in previous studies there was no specific information about the prevalence of CCLR in dogs suffering from leishmaniasis. Theoretically, lameness in leishmaniasis could be produced by polyarthritis, with additional bone or muscle involvement, usually secondary to inflammation associated with the deposition of immune complexes within the joint because of a type III hypersensitivity reaction [4, 12, 30]. However, primary joint infection could also occur, and parasites have been identified within macrophages by cytologic evaluation of the synovial fluid and by histologic assessment of the synovial membranes [31, 32]. Thus, infected dogs could present with monoarthritis, oligoarthritis, or polyarthritis [18], and some reports indicate that stifle joint could be affected in close to 80% of cases [14]. In this study, L. infantum was the most frequent VBP detected in dogs with CCLR, although its prevalence was not significantly different from that in control dogs, suggesting no role of Leishmania infection in the pathogenesis of CCLR. A potential explanation for its detection in both groups of dogs could be the high prevalence of subclinical infection present in an endemic area of leishmaniasis [28, 33].

An association of polyarthritis with ehrlichiosis has been reported previously; however, there was no firm evidence to support it, and other possible co-infections were not ruled out, meaning that the relationship was controversial [10, 15,16,17]. In the present study, three dogs with CCLR were found to have Ehrlichia antibodies or DNA. However, in the two only seropositive dogs, infection could not be confirmed, and perhaps it could simply reflect exposure or past infection. The third dog, seropositive and E. canis PCR-positive, never developed any other clinical sign or laboratory abnormality consistent with patent or subclinical ehrlichiosis, either before or after CCLR surgery. This could imply that this dog perhaps was in an acute stage of the disease and could have recovered alone, or that it was in a subclinical stage. Either of these two scenarios probably rules out a relationship between CCLR and Ehrlichia infection.

Theileria equi is one of the equine piroplasms which is enzootic in Spain, with almost half of the horses having antibodies or circulating parasitemia [34]. This parasite has occasionally been detected in dogs, although its epidemiological and clinical significance remains unknown [35]. All the above, together with the fact that the dog in this study with T. equi in SF did not demonstrate any other clinicopathological abnormalities throughout the study period, could suggest that this pathogen was opportunistic without clinical significance on CCLR.

Although Bartonella, A. phagocytophilum, B. burgdorferi, filariae, or other piroplasms such as Babesia have been associated with acute or chronic canine polyarthritis [10, 13, 17, 19,20,21,22, 36], no dog in this study was positive for any of them. Those findings could be in concordance with the local geographic prevalence of those VBP reported in previous studies in the area evaluated in this study [16, 27, 34, 37]. However, it is worth noting that the limitations regarding the sensitivity of the techniques used and the limitations associated with the specimens collected for testing could also have contributed to failure to detect these organisms.

Lymphoplasmacytic arthritis was the most frequent histopathological finding in this study, in dogs both with and without CCLR. This agrees with previous publications where lymphoplasmacytic synovitis has been commonly described in dogs with CCLR [6], but it has also been detected in post-mortem samples from dogs without CCLR [7]. On the other hand, reactive immune-mediated arthritis due to deposition of developed immune complexes secondary to VBP infection is predominately neutrophilic [4, 11, 12, 18, 29]. This fact reinforces the idea that VBP did not play any role in the pathogenesis of CCLR, together with the fact that neither inflammatory pattern nor frequency of synovitis was statistically different between dogs with or without CCLR or between dogs with or without VBP in this study. However, although not statistically significant, three dogs with CCLR in this study showed granulomatous synovitis, a kind of inflammation also reported in several tissues in dogs with leishmaniasis [33, 38], but only one of them was positive for leishmaniasis. Although granulomatous inflammation is usually associated with the presence of Leishmania within the tissue [12, 13], amastigotes could not be detected in this seropositive and Leishmania PCR-positive dog with granulomatous synovitis. The cause of granulomatous inflammation in the other two dogs remains undetermined. Therefore, the current study could not definitely rule out a potential role of this VBP in the pathogenesis of synovitis and perhaps of CCLR in some of these dogs.

This study has some limitations. The low number of dogs included, due to the difficulty in recruiting cases due to the strict inclusion criteria and the fact that it was a prospective study with a control group, means that the statistical results must be taken with caution. Moreover, only dogs that received CCLR surgical treatment were included, excluding dogs initially diagnosed with VBP and CCLR that ultimately did not undergo surgery. An additional limitation was the wide variety of diseases that led to the euthanasia of control dogs and the fact that articular surfaces were not evaluated, especially knowing that the control population had a higher mean age. However, previous medical histories were extensively evaluated to exclude previous infections with VBP or diseases that could affect the joints. Furthermore, control dogs were also included during the same period and area as CCLR dogs, thus limiting the bias in the probabilities of VBP detection. Finally, the last limitation was the identification of the presence of VBP. In this study we used serology, microscopy in SF cytology, and synovial membrane biopsy, as well as PCR in blood and SF, seeking to maximize the chances of VBP detection. However, the positive serologies were not conclusive of causality of the abnormalities found in the joint. Moreover, it was not possible to perform serology for all the pathogens sought for, nor could immunohistochemistry and/or PCR on the biopsy be performed to increase the probability of detection of selected VBP.

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