Chronic non-bacterial osteomyelitis: a retrospective international study on clinical manifestations and response to treatment.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO. METHODS: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected. RESULTS: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries. CONCLUSIONS: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.

Incidence of infections in patients with psoriatic arthritis and axial spondyloarthritis treated with biological or targeted disease-modifying agents: a systematic review and meta-analysis of randomised controlled trials, open-label studies and observational studies.

OBJECTIVE: To estimate the incidence of infections among patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA), two distinct phenotypes included in the large group of spondyloarthritis (SpA), treated with tumour necrosis-factor-inhibitors, interleukin-17-inhibitors, Janus kinase-inhibitors, IL-23 or IL-12/23-inhibitors (IL-12/23i), phosphodiesterase 4-inhibitors or cytotoxic T-lymphocyte associated protein 4-Ig. METHODS: A meta-analysis of randomised controlled trials (RCTs), open-label extension and observational studies was conducted. Serious infections were defined as infections that were life-threatening, required intravenous antibiotics and/or hospitalisation. Non-serious infections did not meet these severity criteria. The incidence rates (IR) were reported for each diagnosis by treatment class and study type using random-effect model to create a 95% CI. RESULTS: Among 23 333 PsA patients and 11 457 axSpA patients, there were 1.09 serious infections per 100 patient-years (PY) (95% CI 0.85 to 1.35) with similar IR in PsA (0.96 per 100 PY 95% CI 0.69 to 1.28) and axSpA (1.09 per 100 PY 95% CI 0.76 to 1.46). The IR was lower in RCTs (0.77 per 100 PY 95% CI 0.41 to 1.20) compared with observational studies (1.68 per 100 PY 95% CI 1.03 to 2.47). In PsA patients, the lowest IR value was observed with IL-12/23i (0.29 per 100 PY 95% CI 0.00 to 1.03). There were 53.0 non-serious infections per 100 PY (95% CI 43.47 to 63.55) in 7257 PsA patients and 5638 axSpA patients. The IR was higher in RCTs (69.95 per 100 PY 95% CI 61.59 to 78.84) compared with observational studies (15.37 per 100 PY 95% CI 5.11 to 30.97). CONCLUSION: Serious infections were rare events in RCTs and real-life studies. Non-serious infections were common adverse events, mainly in RCTs. PROSPERO REGISTRATION NUMBER: CRD42020196711.

Risk of infections in psoriatic arthritis or axial spondyloarthritis patients treated with targeted therapies: A meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the risk of global infections in patients with psoriatic arthritis (PsA) and axial spondyloarthritis encompassing ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) treated with targeted therapies. METHODS: Medline and Cochrane databases were systematically searched up to March 2021 for randomized controlled trials (RCTs) performed in patients with PsA or axial spondyloarthritis treated with biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Global infections (any infections reported, including bacterial, viral and fungal infections, except serious infections) were the primary outcome. Secondary outcomes included serious infections defined as life-threatening infections or any infection requiring intravenous antibiotics or hospitalization. The relative risk of infections was determined by meta-analysis of RCTs. RESULTS: A total of 60 RCTs were included (20,418 patients), encompassing 17 b/tsDMARDs, compared with placebo, conventional synthetic drugs (csDMARDs) or non-steroidal anti-inflammatory drugs (NSAIDs). An increased risk of any infection for patients exposed to these drugs was found (RR 1.15, 95% CI [1.06-1.25]), mainly with high doses and longer duration of treatment. Most infections were respiratory tract or ear, nose, and throat (ENT) infections. Subgroup analyses showed a statistically significant increased risk of infections for axial spondyloarthritis patients (RR 1.32, 95% CI [1.14-1.52]), but not for PsA patients (RR 1.05, 95% CI [0.97-1.14]). Infection risk was highest with TNF inhibitors (RR 1.23, 95% CI [1.11-1.37]) and IL-17 inhibitors (RR 1.30, 95% CI [1.07-1.59]). No increased risk of serious infections was shown. CONCLUSION: In contrast to serious infections, the risk of global infections is moderately increased with b/tsDMARDs in spondyloarthritis, and is associated in particular with use of TNF and IL-17 inhibitors.

Rheumatoid Arthritis in the View of Osteoimmunology.

Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.