What is the absolute risk of developing diabetes mellitus in patients with glucocorticoid-treated polymyalgia rheumatica and giant cell arteritis? a systematic review and meta-analysis

Background: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are treated with glucocorticoids (GCs) but long-term GC use is associated with diabetes mellitus (DM). The absolute incidence of this serious complication in this patient group remains unclear. Objectives: To quantify the absolute risk of GC-induced DM in PMR and GCA in published literature. Methods: We identified literature from inception to February 2016 reporting diabetes following exposure to oral GC in patients with PMR and/or GCA without preexisting diabetes. A random-effects meta-analysis was performed to summarise the literature. Risk of bias was assessed using the Cochrane Collaboration tool. Results: 21 eligible publications were identified. In studies of patients with GCA, mean cumulative GC dose was almost two times higher than in studies of PMR (8.9g vs 5.0g), with slightly longer treatment duration but much longer duration of follow-up (8.8years vs 4.4years). The incidence proportion (cumulative incidence) of patients who developed new-onset DM was 6% (95% CI: 3–9%) for PMR and 12% (95% CI: 8–17%) for GCA. Heterogeneity between studies was high (I2=78.2%), as there were differences in study designs, patient population, geographical locations and treatment strategies. Based on UK data on incidence rate of DM in the general population1, the expected background incidence rate of DM over 4.4 years in PMR patients and 8.8 years in GCA patients (the duration of follow-up) would be 4.8% and 9.7%, respectively. Very little information on predictors of DM in PMR or GCA patients was found. The overall risk of bias was high for many of the observational studies, especially relating to definition and recording of outcome and prognostic variables. Conclusions: Physicians should screen patients treated for PMR/GCA for DM but it remains unclear what is the time-period of greatest risk and the influence of risk factors. Our meta-analysis produced plausible estimates of DM incidence in patients with PMR and GCA but there is insufficient published data to allow precise quantification of the DM risk or, crucially, which patients are at greatest ris

The prediction and monitoring of toxicity associated with long-term systemic glucocorticoid therapy

Glucocorticoids are often required for adequate control of inflammation in many serious inflammatory diseases; common indications for long-term treatment include polymyalgia rheumatica, giant cell arteritis, asthma and chronic obstructive pulmonary disease. Long-term glucocorticoid therapy is, however, associated with many adverse effects involving skin, gastro-intestinal, eye, skeletal muscle, bone, adrenal, cardio-metabolic and neuropsychiatric systems. This balance between benefits and risks of glucocorticoids is important for clinical practice and glucocorticoid-related adverse effects can significantly impair health-related quality of life. Understanding the nature and mechanisms of glucocorticoid-related adverse effects may inform how patients are monitored for toxicity and identify those groups, such as older people, that may need closer monitoring. For clinical trials in diseases commonly treated with glucocorticoids, standardised measurement of glucocorticoid-related adverse effects would facilitate future evidence synthesis and meta-analysis

Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk

Dr. Conway et al reply

We thank Sauret et al for their interest in our systematic literature review that explored potential diagnostic confusion between giant cell arteritis (GCA) and the coronavirus disease 2019 (COVID-19). This was a particularly important consideration during the early months of the COVID-19 pandemic, when community testing for SARS-CoV-2 was limited and diagnostic tests for GCA were restricted or unavailable due to redeployment of staff.</p

Dr. Conway et al reply

We thank Sauret et al for their interest in our systematic literature review that explored potential diagnostic confusion between giant cell arteritis (GCA) and the coronavirus disease 2019 (COVID-19). This was a particularly important consideration during the early months of the COVID-19 pandemic, when community testing for SARS-CoV-2 was limited and diagnostic tests for GCA were restricted or unavailable due to redeployment of staff.</p

Preliminary concurrent validity of the Fitbit-Zip and ActiGraph activity monitors for measuring steps in people with polymyalgia rheumatica

Background Activity monitors provide objective measurements of physical activity, however, the accuracy of these devices in people with polymyalgia rheumatica (PMR) is unknown. Therefore, this study aimed to obtain preliminary evidence of the accuracy of two activity monitors and explore if clinical and gait-related factors altered device accuracy in people with PMR. Methods The ActiGraph with low frequency extension (+LFE) and standard (-LFE) algorithms, Fitbit-Zip (waist) and Fitbit-Zip (shirt) were concurrently tested using a two-minute walk test (2MWT) and stairs test in 27 people with PMR currently treated with prednisolone. To determine accuracy, activity monitor step-count was compared to a gold-standard step-count (GSSC; calculated from video recording) using Bland-Altman plots. Results The Fitbit-Zip (waist) achieved closest agreement to the GSSC for the 2MWT (mean bias (95%CI): 10 (-3, 23); 95%LOA: −55, 74). The ActiGraph (+LFE) achieved closest agreement to the GSSC for the stairs test (mean bias (95%CI): 0 (-1, 1); 95%LOA: −5, 5). The ActiGraph (-LFE) performed poorly in both tests. All devices demonstrated reduced accuracy in participants with lower gait velocity, reduced stride length, longer double-limb support phase and greater self-reported functional impairment. Conclusion Our preliminary results suggest that in controlled conditions, the Fitbit-Zip fairly accurately measures step-count during walking in people with PMR receiving treatment. However, device error was greater than data published in healthy people. The ActiGraph may not be recommended without activation of the LFE. We identified clinical and gait-related factors associated with higher levels of functional impairment that reduced device accuracy. Further work is required to evaluate the validity of the activity monitors in field conditions

Polymyalgia rheumatica shows metabolomic alterations that are further altered by glucocorticoid treatment:Identification of metabolic correlates of fatigue

OBJECTIVE: In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA).METHODS: Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms.RESULTS: The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R2 &gt; 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R2 = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R2 = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R 2 ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R2 &gt; 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change). CONCLUSION: PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.</p

FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

OBJECTIVE:The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. METHODS:FcγRIIIa/CD16 expression on CD14(low) and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. RESULTS:Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. CONCLUSION:Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy