Discussion
Arthralgia and musculoskeletal pain associated with denosumab are
usually mild and transient, and is not typically associated with a
systemic inflammatory response.4 Denosumab has been
noted to cause flares of known PMR,6 but has not been
associated with causing new-onset PMR. Denosumab has been studied in
populations with RA for treatment of steroid-induced osteoporosis, and
has not been noted to worsen or cause new-onset inflammatory
arthritis.8-10
We present a case of an elderly patient with new-onset seropositive
inflammatory arthritis following denosumab therapy. Using the Naranjo
scale,11 this case scored five points, making this a
probable association. A literature search using terms “denosumab”,
“polymyalgia rheumatica”, “rheumatoid arthritis” and “inflammatory
arthritis” on PubMed, Scopus and Google Scholar databases did not
report any similar cases. Hence, this represents the first case report
of newly-diagnosed seropositive inflammatory arthritis associated with
denosumab.
The diagnosis of late-onset seropositive RA best encapsulates the
presentation of inflammatory arthritis in the setting of elevated RF and
ACPA. However, the patient presented with typical features of PMR
including shoulder and hip girdle involvement, with relative sparing of
small joints. The subscapularis and supraspinatus pathologies (Figure 1)
in this patient are in keeping with ultrasound findings in
PMR,12 although subdeltoid subacromial bursitis and
long head of biceps tendinopathy are typically seen.12There was no evidence of extra-articular manifestations of RA. The
patient appeared to have exquisite response to low-dose prednisolone,
which is characteristic of PMR7.
We postulate that the patient had pre-existing RA autoantibodies and
subclinical disease that was unmasked by denosumab therapy. The patient
was an ex-smoker, and in genetically susceptible patients, smoking is a
well-recognised trigger for self-protein citrullination and autoantibody
production–from which RA pathogenesis stems.13 The
patient also had osteoporosis, which is associated with
RA.13
RF is an autoantibody against the crystallisable fraction portion of
human immunoglobulin G (IgG) and plays a pathogenic role in
RA.14 In this case, we postulate that denosumab–a
fully human IgG molecule1–may have acted as an
antigen that was recognised by the patient’s pre-existing autoreactive
B-cell repertoire, which subsequently triggered aberrant RF autoantibody
production and immune complex formation–resulting in the disease
flare.14 However, the precise mechanism of how
denosumab would cause an inflammatory arthritis flare is unclear. Future
research could involve observational studies looking for severe
autoimmune adverse effects to denosumab, with further investigation of
the underlying molecular mechanisms of this adverse reaction.
We cannot disprove that the administration of denosumab and arthritis
flare were coincidental. However, we think this is very unlikely given
the time course of the patient receiving denosumab on the same day prior
to symptom onset, and being completely well prior to treatment. We
believe this case represents a first flare of seropositive inflammatory
arthritis secondary to denosumab, which exceeds the arthralgia and
musculoskeletal pain adverse effects previously
reported.2,6
Interestingly, despite denosumab being studied in RA populations, no
flares have been reported.8-10 We postulate that this
is because in those studies, all patients already had RA diagnosed and
were on at least low-dose prednisolone immunosuppressive therapy as part
of inclusion criteria.8-10 Thus, such therapy may have
mitigated any potential flares induced by denosumab. This is supported
by the exquisite response to low-dose prednisolone observed in our
patient. Alternatively, denosumab-induced inflammatory arthritis flares
may be a very rare event that was not observed in the studies.
In summary, we present a case of newly-diagnosed seropositive
inflammatory arthritis flaring after initiating denosumab therapy. This
case highlights the need to closely monitor for adverse effects in
patients, and consider this rare adverse effect of seropositive
inflammatory arthritis in patients who develop severe, progressive
arthralgia and musculoskeletal pain after starting denosumab.