DISCUSSION
IA corticosteroids have been the most used treatment for articular
lesions for years; however, this is a controversial therapy. This
systematic review gathered data regarding its effects on joints
(McIlwraith & Lattermann, 2019; Velloso Alvarez et al., 2020; Boorman
et al., 2022). The evidence suggests that 1) single IA corticosteroid
injections in OA joints tend to show higher effectiveness in SMOA in
studies with shorter follow-ups or at periods shorter than the follow-up
proposed. DMOA showed no consistent adverse effects, varying according
to corticosteroids. Nevertheless, some conflicting results were within
the same corticosteroid type across studies. 2) Corticosteroids appear
not to induce symptomatic changes in normal joints in horses, although
adverse changes to joint tissues (cartilage or SM) and metabolism are
usually found. A dose effect, where lower doses have better—or less
detrimental—responses, was found in in vitro studies of normal
equine articular tissues. The risk of bias in included studies was
mainly unclear because the authors did not report the entire
methodology. For example, it was not reported whether groups were
randomized, and if so, what was the randomization method. Therefore,
whether the study presents bias arising from selection, performance,
detection, attrition, or reporting is unclear. Despite being implied at
times, a clear description of methods should always be included, even if
it sounds repetitive. Reporting guidelines for different study designs
are currently available. By following these, authors can achieve a lower
risk of bias, improving study quality and (consequently) reliable data.
A single injection of corticosteroids for OA joints was evaluated to
answer question 1. Articles investigating such topics were more common
in humans, where the primary outcomes were usually PROMs. SMOA effects
tended to show improvements in shorter follow-ups, having positive
effects reported in up to three weeks in horses (lameness) and 3–12
weeks in humans. Beyond this period, one study found detrimental effects
to SMOA in horses (de Clifford et al., 2021), while in humans, drawbacks
were limited to the loss of positive effects. Despite sharing
similarities in the disease process, this finding may point to the
possible divergent responses in different species and emphasizes the
need for species-specific studies to ensure the application of findings
in clinical settings.
Regarding DMOA changes after single injections in OA joints, outcome
measures varied according to the corticosteroid; however, in vivoor clinical studies including these outcomes were more scarce than ones
including SMOA effects. Findings usually represent changes in joint
metabolism, indicating possible disease progression rather than linking
the disease progression to corticosteroids. For example, changes from
imaging tools were conflicting, ranging from significantly higher
chances of joint deterioration to no significant risk of worsening of
disease progression compared to controls (Okike et al., 2021; Latourte
et al., 2022). A positive effect seen in radiographs was only found for
TH in one study, in which patients showed disease progression at a
significantly lower rate than controls (Nunes-Tamashiro et al., 2022).
Other DMOA changes included SF WBC counts (conflicting results for TA
with no changes for MPA), negative results such as increasing synthesis
of smaller PG (MPA) inducing changes in chondrocytes phenotype (MPA),
transiently increasing GAG concentrations in SF (TA), and increasing in
PGE2 concentrations in SF (TA). Positive DMOA were
decreases in SF TP (TA), decreases in CCL2 and MMPs activity (TA), and
improvements in SM immunohistochemistry (MPA). No other significant
changes were found in DMOA of horses or humans injected with
corticosteroids for OA treatment.
The effects of corticosteroid exposure on normal joints were also
investigated. As expected for any therapy, corticosteroids (MPA and TA)
did not cause lameness or joint effusion when these were investigated in
three studies (Murray et al., 1998; Robion et al., 2001; Céleste et al.,
2005). However, some adverse effects on normal joints were found when
MPA and TA were evaluated in vivo . Outcome measures were usually
those that can demonstrate disturbances in homeostasis (WBC, TP, PG,
GAG, and HA concentrations in SF, PG synthesis in cartilage, biomarkers,
and gene expression in SF) while some also showed adverse changes in
histology and histochemistry of SM and cartilage and biomechanics of
cartilage (Frisbie et al., 1997; Murray et al., 1998; Frisbie et al.,
1998). At such levels, more modest positive changes could also be found
compared to controls (improvements in histology of cartilage and SM, GAG
metabolism and synthesis for TA, improvements in collagen and protein
synthesis in cartilage and SM, and increases in lubricating surfactant
secretion for MPA). In vitro , adverse effects were common for all
corticosteroid types (MPA, BTM, DEX, and TA). These included impairments
of cartilage metabolism (synthesis and degradation) with usually
dose-dependent effects, where lower doses were associated with less
detrimental changes.
Effects of medications on normal joints are usually performed to assess
the therapy’s safety; however, findings are frequently extrapolated to
clinical use in diseased joints. Although this makes sense, the
environment of healthy and osteoarthritic joints is highly divergent;
therefore, they may behave differently when exposed to therapy. For
example, Todhunter et al. (1998) found that the inhibition of PG
synthesis in healthy joints exposed to corticosteroids was not present
in lipopolysaccharide-induced joints treated the same way. This finding
was also seen in Frisbie et al. (1997), in which GAG content in SF was
significantly higher in normal joints exposed to TA but not
significantly different from controls when surgically induced joints
were treated similarly. Accordingly, some differences in the effects of
MPA in healthy and diseased joints were found by Frisbie et al. (1998).
This finding suggests that results from normal and diseased joints
differ and should not be considered together.
Limitations of this review include heterogeneity of included studies and
employed treatment protocols, which hamper comparisons and unclear risk
of bias for most of the results presented.
CONCLUSION
Evidence gathered in this review was mainly rated as unclear risk of
bias. Our findings suggest that 1) single IA corticosteroid injections
tend to show higher effectiveness in SMOA in studies with shorter
follow-ups, while DMOA varied according to corticosteroid with
conflicting results regarding the same type of corticosteroid across
studies. 2) Corticosteroids do not induce symptomatic changes in normal
joints of horses despite adverse effects on joint tissues and
metabolism. This finding could indicate pathways that might lead to
detrimental effects on joint health; however, direct changes are
lacking. A dose-dependent effect, where lower doses have better—or
less detrimental—responses, was found in in vitro studies of
normal equine articular tissues.