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.