Standardisation of ACPA tests: evaluation of a new candidate reference preparation.

INTRODUCTION: Commercial assays measuring antibodies to citrullinated protein/peptide (ACPA) show poor quantitative agreement. The diagnostic industry has never adopted the International Union of Immunological Societies-Centers for Disease Control and Prevention (IUIS-CDC) ACPA reference standard. Recently, the National Institute for Biological Standards and Control (NIBSC) prepared a new candidate ACPA standard (18/204). We evaluated both reference materials using different commercially available ACPA assays. MATERIALS AND METHODS: This is an international study in which the NIBSC candidate ACPA standard and the IUIS-CDC ACPA reference material were analysed together with 398 diagnostic samples from individuals with rheumatoid arthritis (RA) and in 1073 individuals who did not have RA using nine commercial ACPA assays. RESULTS: For both reference materials and samples from individuals with RA and individuals who did not have RA, there were large differences in quantitative ACPA results between assays. For most assays, values for the IUIS-CDC standard were lower than values for NIBSC 18/204 and the IUIS-CDC/NIBSC ratio was comparable for several, but not all assays. When NIBSC 18/204 was used as a calibrator, an improvement in alignment of ACPA results across several of the evaluated assays was obtained. Moreover, NIBSC 18/204 could align clinical interpretation for some but not all assays. CONCLUSION: Adoption of an international standard for ACPA determination is highly desirable. The candidate NIBSC 18/204 standard improved the standardisation and alignment of most ACPA assays and might therefore be recommended to be used as reference in commercial assays.

IgA rheumatoid factor in rheumatoid arthritis.

OBJECTIVES: Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context. METHODS: An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available. RESULTS: The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjögren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies. CONCLUSIONS: IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.

The Role of Physicians' Digital Tools in Pharmacological Management of Type 2 Diabetes Mellitus.

Background and Objectives: The constantly increasing prevalence of type 2 diabetes mellitus (T2DM) and the advent of new treatment options have made management of T2DM patients more demanding. We aimed to (a) estimate the familiarity of general practitioners with novel T2DM treatment options, (b) determine whether a digital tool can aid in their treatment decisions and (c) demonstrate that an evidence-based digital clinical support tool can be made using an existing digital platform. Materials and methods: This proof-of-concept study consisted of two parts: We first conducted a simple online survey among general practitioners of three European countries to estimate their familiarity with novel T2DM treatment options and to determine whether they believe that a digital tool can aid in their T2DM treatment decisions. We then proceeded to develop a new digital tool that provides quick, evidence-based support for treatment of patients with T2DM using an existing digital platform. Results: The online survey was completed by 129/5278 physicians (94 from Italy, 22 from Czech Republic and 13 from Slovenia). Only 30.7% of all general practitioners reported to be either very or extremely familiar with novel T2DM treatments; the vast majority of participating general practitioners (82.8%) reported that they would find a digital clinical decision support tool for treating T2DM patients either very or extremely useful. A digital tool which features the characteristics deemed most important by the polled physicians was subsequently developed. Conclusions: The results of the online survey showed that familiarity of general practitioners with novel T2DM treatment options is relatively low and that there is a need for digital clinical decision support tools intended to facilitate treatment decisions in T2DM patients. We demonstrated that such a tool can easily be developed using an existing digital platform.

The cut-off values for the intima-media complex thickness assessed by colour Doppler sonography in seven cranial and aortic arch arteries.

OBJECTIVES: Colour Doppler sonography (CDS) is becoming ever more important in the diagnosis of GCA. Data on cut-off values for intima-media complex thickness (IMT) that can be used in clinical practice to distinguish between normal and inflamed arteries are limited. We aimed to derive potential cut-off values for IMT of seven preselected arteries by comparing IMT between GCA patients and a control group. METHODS: We performed CDS of the preselected temporal, facial, occipital, carotid, vertebral, subclavian and axillary arteries in consecutive newly diagnosed GCA patients between October 2013 and September 2019. A 'halo' with positive compression sign was considered a positive finding. We measured the maximum IMT in the preselected arteries and compared it with the maximum IMT of the control group. RESULTS: We were able to demonstrate a halo sign in at least one of the examined arteries of 244/248 (98.4%) GCA patients. Temporal arteries were the most commonly affected vessels, involved in 192 (77.4%) patients. We found extracranial large vessel involvement in 87 (35.1%) patients. The following cut-off values showed high levels of diagnostic accuracy: ≥0.4 mm for temporal, facial and occipital arteries, ≥0.7 mm for vertebral arteries, and ≥1 mm for carotid, subclavian and axillary arteries. CONCLUSION: The involvement of a large array of arteries is easily and commonly detected by CDS and provides a high diagnostic yield in patients with suspected GCA. Proposed IMT cut-off values might further improve the diagnostic utility of CDS in these patients.

Risk factors for severe cranial ischaemic complications in giant cell arteritis.

OBJECTIVES: Vision complications and a stroke represent severe cranial ischaemic complications (sCIC) associated with increased morbidity and mortality in GCA. We aimed to determine the risk factors for sCIC in GCA. METHODS: We analysed the medical records of prospectively enrolled GCA patients diagnosed between September 2011 and August 2019, and compared the clinical and laboratory characteristics of patients with and without sCIC defined as either severe vision complications (diplopia, transient vision loss, permanent partial vision field/acuity defect and permanent visual loss) or stroke. RESULTS: During the 96-month observation period, we identified 295 new GCA patients [65.4% female, median (interquartile range) age 74.7 (67.3-80.0) years]. Sixty-one (20.7%) patients developed sCIC (52 isolated severe vision complications, 5 isolated ischaemic strokes and 4 patients with both complications). In a multivariable logistic regression model jaw claudication [odds ratio (OR) 3.43 (95% CI: 1.84, 6.42), P < 0.001], smoking [OR 1.92 (95% CI: 1.01, 3.65), P = 0.046] and increasing age [OR 1.08 (95% CI: 1.04, 1.13), P < 0.001] were significantly associated with sCIC. Higher CRP [OR 0.99 (0.99-1.00), P = 0.011] decreased the risk of sCIC. When considered separately, the odds for severe vision complications increased with age and jaw claudication, and decreased with polymyalgia rheumatica, constitutional symptoms and higher CRP. Atrial fibrillation emerged as the sole independent predictor of ischaemic stroke. CONCLUSION: Increasing age, jaw claudication and smoking predicted sCIC, while higher CRP decreased the risk of sCIC in our GCA cohort.

COVID-19 among patients with giant cell arteritis: a single-centre observational study from Slovenia.

OBJECTIVES: Patients with giant cell arteritis (GCA) represent a fragile population with an increased infection risk. In a recent study, older age, a higher number of comorbidities, higher disease activity and prednisolone ≥ 10 mg/day were associated with worse COVID-19 outcome. We aimed to evaluate the frequency and severity of COVID-19 in a well-defined GCA cohort. METHODS: We reviewed medical records of histologically and/or by imaging-proven GCA patients diagnosed between September 2011 and February 2020 at our secondary/tertiary centre and followed during the COVID-19 pandemic between March 2020 and February 2022 (24 months). Descriptive statistics were used to explore the studied population. RESULTS: Of 314 patients with GCA diagnosed for the first time during a 102-month period, 49 patients died before March 2020. Of the remaining 265 patients, 55 (20.8%) patients suffered from a total of 57 SARS-CoV-2 infections. We observed 44 (77.2%) mild and 13 (22.8%) severe COVID-19 episodes (the latter defined as needing hospitalization, death or thrombotic complication). Patients with severe COVID-19 were more likely to have arterial hypertension (12 [92.3%] vs. 25 [56.8%]; p = 0.022), cardiovascular disease (7 [53.8%] vs. 10 [22.7%]; p = 0.043) or obesity (5 [38.5%] vs. 5 [11.4%]; p = 0.038). Neither prednisolone dose 1-5 mg/day (p = 0.483) nor leflunomide use (p = 1.000) was associated with COVID-19 course. There were no significant differences in sex, age, GCA type, GCA disease duration and other comorbidities in patients with mild and severe COVID-19 in our cohort. CONCLUSION: More than a fifth of our GCA patients had severe COVID-19. Treatment with leflunomide or low doses of glucocorticoids were not associated with severe course in our cohort. Key Points • Treatment with leflunomide or low doses of glucocorticoids were not associated with worse COVID-19 outcome. • Outcomes of COVID-19 improved as the COVID-19 pandemic, prevention and treatment options evolved. • Arterial hypertension, cardiovascular disease or obesity were associated with severe COVID-19.

Multicentre study to improve clinical interpretation of rheumatoid factor and anti-citrullinated protein/peptide antibodies test results.

BACKGROUND: Rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) are important biomarkers for diagnosis of rheumatoid arthritis (RA). However, there is poor harmonisation of RF and ACPA assays. The aim of this study was to refine RF and ACPA interpretation across commercial assays. MATERIALS AND METHODS: Six total RF isotype-non-specific assays, 3 RF IgM isotype-specific assays and 9 ACPA immunoglobulin G assays of 13 different companies were evaluated using 398 diagnostic samples from patients with RA and 1073 disease controls. RESULTS: Using cut-offs proposed by the manufacturer, there was a large variability in diagnostic sensitivity and specificity between assays. Thresholds of antibody levels were determined based on predefined specificities and used to define test result intervals. Test result interval-specific likelihood ratios (LRs) were concordant across the different RF and ACPA assays. For all assays, the LR for RA increased with increasing antibody level. Higher LRs were found for ACPA than for RF. ACPA levels associated with LRs >80 were found in a substantial fraction (>22%) of patients with RA. CONCLUSION: Defining thresholds for antibody levels and assigning test result interval-specific LRs allows alignment of clinical interpretation for all RF and ACPA assays.

Does leflunomide have a role in giant cell arteritis? An open-label study.

Glucocorticoid monotherapy has been the mainstay treatment of giant cell arteritis (GCA) for decades. We aimed to evaluate the role of leflunomide as a steroid-sparing agent in GCA. This open-label study included incipient GCA patients followed for at least 48 weeks at a single secondary/tertiary rheumatology centre. At the time of diagnosis, patients received glucocorticoids. At week 12 of follow-up, leflunomide 10 mg qd was recommended as an adjunctive therapy to all patients without contraindications. The decision to start the leflunomide was patient-dependent. The number of relapses, a cumulative glucocorticoid dose during follow-up and treatment-related adverse events (AE) were recorded and compared between glucocorticoid-only and leflunomide groups. Seventy-six patients (65.8% female, median (IQR) age 73.7 (66.1-78.8) years) were followed for a median (IQR) 96 (86-96) weeks. Thirty out of 76 (39.5%) patients received leflunomide at week 12 (leflunomide group); the others continued treatment with glucocorticoid (glucocorticoid-only group). During the first 48 weeks of follow-up, 22 patients relapsed, 4 (13.3%) in leflunomide group and 18 (39.1%) in glucocorticoid-only group. The difference was statistically significant (p = 0.02; NNT 3.9 (95% CI 2.2-17.4)). Furthermore, 17/30 (56.7%) patients in the leflunomide group managed to stop glucocorticoid at week 48 (with one relapse (5.9%) shortly afterwards). The cumulative glucocorticoid dose at the last visit was lower in the leflunomide group than in the glucocorticoid-only group (p = 0.01). Our findings indicate the steroid-sparing effect of leflunomide in GCA.

The incidence of spondyloarthritis in Slovenia.

Epidemiological studies of spondyloarthritides (SpA) are rare and data for our country are lacking. We aimed to determine the incidence of SpA in a well-defined region in Slovenia.We performed a retrospective chart review of adults diagnosed with SpA between January 2014 and December 2016 at an integrated secondary/tertiary medical center, which provides rheumatology services to almost a half of the adult national population, that is, 700,000 adults. Potential cases were ascertained by searching the electronic medical records for ICD-10 codes M02, M07, M13, M45, M 46.1, K50, K51, and L40. SpA cases were stratified as axial and peripheral SpA and then the annual incidence rates of SpA overall and both subsets were estimated.During the 3-year period we identified 302 SpA cases (55.0% males, median [interquartile range] age 46.7 [35.0-57.5] years). 98 (32.5%) of them had predominantly axial SpA and the remainder peripheral SpA. The estimated annual incidence rate per 100,000 adults in our region was 14.3 (95% confidence interval [CI] 12.8-16.0) for SpA overall, 4.6 (95% CI 3.8-5.6) for axial SpA, and 9.6 (95% CI 8.4-11.1) for peripheral SpA.The estimated annual incidence rate of 14.3 cases per 100,000 adults in SpA overall was comparable to that of rheumatoid arthritis in our population. The peripheral SpA was twice as common as axial SpA.

The incidence rate and the early management of rheumatoid arthritis in Slovenia.

Epidemiological data for rheumatoid arthritis (RA) differ according to ethnicity and geographical region. Moreover, despite of clear RA management guidelines, the implementation of treat-to-target (T2T) strategy often remains incomplete. Our objectives were to determine the incidence rate of RA, the clinical characteristics, and the level of adherence to the T2T guidelines in Slovenia. We analyzed prospectively the collected data of adult patients diagnosed with RA from 2014 through 2016 at the Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia. The department provides rheumatology services to a well-defined region with a population of 704,000 adult residents. During the 3-year observation, we identified 341 incipient cases of RA (75% females, median (IQR) aged 64 (52.0-75.4) years), resulting in an annual incidence rate of 16.1 per 100,000 adults (95% CI 14.5-17.9). The incidence rate peaked in the 70-79-year age interval. The median time from the onset of symptoms suggestive of RA to rheumatology consultation was 12.9 (4.4-26.1) weeks, and the median time from referral to consultation was 1 (1-3) day. Within 12 weeks of symptom onset, 161 (47.2%) incipient RA patients were examined by a rheumatologist, and 123 (36.1%) were started on DMARD therapy. The estimated incidence rate was in line with the available epidemiological data. Our early interventional clinic enabled us to identify and manage a substantial portion of RA patients within the recommended time frame.

The incidence of giant cell arteritis in Slovenia.

Giant cell arteritis (GCA) is the most common vasculitis in adults aged ≥ 50 years in Europe. Recently, colour Doppler ultrasonography (CDS) and positron emission tomography-computed tomography (PET/CT) have improved the diagnostic sensitivity. The aim of our study was to determine the incidence of GCA in a well-defined Slovenian region, supported by the temporal artery (TA) biopsy (TAB) or CDS or PET/CT. This prospective study was conducted at the University Medical Centre Ljubljana, the only secondary/tertiary centre in the region, serving a population of 323,297 residents aged ≥ 50 years. Patients with suspected GCA are referred either to the Department of Rheumatology, or in case of severe visual disturbances, to the Department of Ophthalmology. We included all GCA cases diagnosed between 1 January 2012 and 31 December 2017. We diagnosed cranial GCA (c-GCA) using the American College of Rheumatology (ACR) 1990 classification criteria and a positive TAB or TA-CDS. Large vessel GCA (lv-GCA) was diagnosed using CDS or PET/CT. During the 6-year observation, we identified 169 incipient GCA cases (66.3% female, median (IQR) age of 75.1 (68.6-80.0) years). Forty-two (24.8%) patients had lv-GCA, and the others had c-GCA. The estimated annual incidence rates of GCA were overall 8.7 (95% CI 7.5-10.1), c-GCA 6.5 (95% CI 5.5-7.8) and lv-GCA 2.2 (95%CI 1.6-2.9) per 100,000 aged ≥ 50 years. GCA is the most common vasculitis in adults aged ≥ 50 years, with an annual incidence rate of 8.7 per 100,000.

Utility of serological biomarkers for giant cell arteritis in a large cohort of treatment-naïve patients.

Early diagnosis and treatment of giant cell arteritis (GCA) is crucial for preventing ischemic complications. Multiple serological markers have been identified; however, there is a distinct lack of predicting markers for GCA relapse and complications. Our main objective was to identify serological parameters in a large cohort of treatment-naïve GCA patients, which could support clinicians in evaluating the course of the disease. Clinical data was gathered, along with analyte detection using Luminex technology, ELISA, and nephelometry, among others. Unsupervised hierarchical clustering and principal component analysis of analyte profiles were performed to determine delineation of GCA patients and healthy blood donors (HBDs). Highest, significantly elevated analytes in GCA patients were SAA (83-fold > HBDs median values), IL-23 (58-fold), and IL-6 (11-fold). Importantly, we show for the first time significantly changed levels of MARCO, alpha-fetoprotein, protein C, resistin, TNC, TNF RI, M-CSF, IL-18, and IL-31 in GCA versus HBDs. Changes in levels of SAA, CRP, haptoglobin, ESR, MMP-1 and MMP-2, and TNF-alpha were found associated with relapse and visual disturbances. aCL IgG was associated with limb artery involvement, even following adjustment for multiple testing. Principal component analysis revealed clear delineation between HBDs and GCA patients. Our study reveals biomarker clusters in a large cohort of patients with GCA and emphasizes the importance of using groups of serological biomarkers, such as acute phase proteins, MMPs, and cytokines (e.g. TNF-alpha) that could provide crucial insight into GCA complications and progression, leading to a more personalized disease management.

The role of colour doppler ultrasonography of facial and occipital arteries in patients with giant cell arteritis: A prospective study.

OBJECTIVE: Colour Doppler Sonography (CDS) in giant cell arteritis (GCA) allows the study of involvement of cranial arteries other than the temporal arteries, which are inconvenient to biopsy, such as the facial (FaA), and occipital (OcA) arteries. We aimed to estimate the frequency of the FaA, and OcA involvement in GCA; and to explore the clinical characteristics of these subgroups of patients. METHODS: From 1 January 2014 to 31 December 2016 we prospectively performed a CDS of the FaA, and OcA in addition to the temporal (TA), and the extracranial supra-aortic arteries in all newly diagnosed patients suspected of having GCA. All the arteries were evaluated in two planes for the highly specific halo sign. RESULTS: During the 36-month observation period we performed a CDS of the cranial and extra-cranial arteries in 93 GCA patients. We observed the halo sign on the FaA, and OcA in 38 (40.9%), and 29 (31.2%) cases, respectively. The FaA, or OcA were affected in 4/22 (18.2%) patients with a negative TA CDS. FaA involvement significantly correlated with jaw claudication and with severe visual manifestations, including permanent visual loss. CONCLUSIONS: A fifth of patients with a negative CDS of the TAs had signs of vasculitis on the CDS of the FaA, or OcA. The addition of FaA and OcA CDS to the routine CDS of the TAs could identify 4.3% more patients and thus further improve the sensitivity of the CDS in the suspected GCA.

Do Early Diagnosis and Glucocorticoid Treatment Decrease the Risk of Permanent Visual Loss and Early Relapses in Giant Cell Arteritis: A Prospective Longitudinal Study.

To determine the incidence of permanent visual loss (PVL) in giant cell arteritis (GCA) and the GCA relapse rate during glucocorticoid (GC) tapering.This prospective, longitudinal single secondary/tertiary rheumatology centre study was conducted between September 2011 and September 2014 in Slovenia. Predetermined clinical and laboratory tests were performed at 12, 24, 48, 96, and 144 weeks after diagnosis.Sixty-eight GCA patients (72.1% female), with a median (IQR) age of 73.2 (67.3-76.1) years and a symptom duration before the diagnosis of a median (IQR) 30 (14-70) days were included. Thirty-nine of 68 patients had symptoms for less than 31 days (14 (10-28) days-early GCA) and 29/68 for 31 days or longer (90 (60-120) days-late GCA). Four (5.9%) patients presented with PVL (1 early GCA). The median (IQR) follow-up was (IQR) 104 (53-126) weeks. GCA relapsed in 17/39 (43.6%) and 14/29 (48.3%) in early and late GCA, respectively. The median (IQR) time to the first relapse was 24.8 (13.6-46.5) weeks (early GCA 14 (13-34) weeks; late GCA 25 (22-48) weeks, P = 0.117), at the methyl-prednisolone dose of 6.0 (4.0-12.0) mg. The patients who relapsed had significantly higher levels of inflammation parameters at the baseline (including ESR, CRP, serum amyloid A, haptoglobin, and fibrinogen).An early GCA diagnosis and prompt GC treatment decreased the PVL rate in comparison to historic controls, but seem to have no impact on the frequency of relapses, which are predicted by the high baseline levels of the biomarkers of inflammation.

A case of inverse psoriasis successfully treated with adalimumab.

Inverse psoriasis is a rare form of psoriasis characterized by the involvement of skin fold areas rather than the more common psoriatic involvement of the extensor surfaces of the extremities, trunk, and scalp. In addition, it requires a modified therapeutic approach because it is often less responsive to standard treatment regimens. Current treatment recommendations for inverse psoriasis mainly consist of topical agents, including corticosteroids, calcipotriol, and immunomodulating agents, whereas systemic medications remain insufficiently studied. Although adalimumab, a TNF-α inhibitor, has been approved for the treatment of moderate to severe plaque psoriasis, some reports indicate that TNF-α inhibitors may sometimes trigger psoriatic lesions, including inverse psoriasis. However, we present a case of inverse psoriasis and psoriatic arthritis unresponsive to standard treatment that was successfully treated with adalimumab.