Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and, in many cases, destruction of the joints. To prevent progressive and irreversible structural damage, early ...diagnosis of RA is of paramount importance. The present study addresses the search of new RA citrullinated antigens that could supplement or complement diagnostic/prognostic existing tests. With this aim, the epitope anticitrullinated vimentin antibody response was mapped using synthetic peptides. To improve the sensitivity/specificity balance, a vimentin peptide that was selected, and its cyclic analogue, were combined with fibrin- and filaggrin-related peptides to render chimeric peptides. Our findings highlight the putative application of these chimeric peptides for the design of RA diagnosis systems and imply that more than one serological test is required to classify RA patients based on the presence or absence of ACPAs. Each of the target molecules reported here (fibrin, vimentin, filaggrin) has a specific utility in the identification of a particular subset of RA patients.
Aims
Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing ...strategy and provide a scientific rational for dosing using a modelling and simulation approach.
Methods
Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 103 μg h ml–1.
Results
A one‐compartment disposition model with parallel linear and nonlinear elimination best described the concentration–time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis–Menten constant were 0.0104 l h–1, 4.83 l, 0.239 mg h–1 and 4.22 μg ml–1, respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C‐reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight‐based dosing approach is used. However, fixed‐dosing provides a more consistent drug exposure regardless of weight category.
Conclusions
Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight‐based dosing approach.
Undifferentiated arthritis (UA) is defined as an inflammatory arthritis that does not fulfill criteria for a definite diagnosis. Delay in reaching a specific diagnostic and therapy may lead to ...impaired functional outcomes. Our aim was to identify synovial biomarkers associated with definitive diagnostic classification in patients with UA.
DMARD-naïve UA patients with available initial synovial tissue (ST) and a final diagnosis of rheumatoid arthritis (RA) or psoriatic arthritis (PsA) during follow-up were included and compared with patients with well-defined disease (RA or PsA). Clinical, arthroscopic, and pathological data were compared between groups. Pathology included quantitative immunohistochemical (IHC) analysis of cell types and human interferon-regulated MxA. Principal component analysis (PCA) was performed to extract disease patterns.
One hundred and five patients were included: 31 patients with DMARD-naïve UA (19 evolving to RA and 12 to PsA during a median follow up of 7 years), 39 with established RA, and 35 with established PsA. ST from the UA group showed higher macrophage density compared with the established RA and PsA groups. Patients with UA evolving to RA (UA-RA) showed higher MxA expression and CD3
T-cell density compared with established RA. UA patients evolving to PsA (UA-PsA) showed increased vascularity and lining synovial fibroblast density compared with established PsA. Synovitis of UA-PsA patients showed more mast cells and lining fibroblasts compared with UA-RA. No between-group differences in local or systemic inflammation markers were found.
Our results show differences in the cellular composition of UA synovium compared with RA and PsA, with higher density of the cellular infiltrate in the UA groups. Initial expression of the interferon inducible gene MxA could be a biomarker of progression to RA, while higher mast cell and fibroblastic density may be associated with PsA progression.
Introduction: Tumor necrosis factor inhibitors (TNFi) were the first biologic therapy authorized for rheumatoid arthritis (RA) treatment and are currently the most used biological drugs in these ...patients. Although clinical efficacy is proven, adverse events associated with these agents have been described, and further knowledge is essential to facilitate detection at very early stages.
Areas covered: We reviewed the safety profile of TNFi, including both articles and congress communications published on this topic, such as clinical trials, meta-analyses, observational studies, data from registries, and spontaneous clinical reports. We classified studies according to the most common and relevant adverse events associated with TNFi.
Expert opinion: There is a broad spectrum of possible adverse events associated with TNFi treatment, ranging from mild to serious, and with diverse clinical manifestations. However, most adverse events may be minimized by appropriate screening before starting treatment and with ongoing surveillance to ensure an early diagnosis. In conclusion, TNFi have a reasonable safety profile, and, globally, the benefits far outweigh the possible risk of adverse events, especially compared with the risk of the untreated underlying inflammatory condition.
Objective
To analyze the incidence rate (IR) and risk factors of cutaneous adverse events (CAE) in patients with chronic inflammatory rheumatic diseases treated with tumor necrosis factor (TNF) ...antagonists.
Methods
We analyzed all patients from the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) registry treated with a TNF antagonist (infliximab, etanercept, or adalimumab). Data collected included age, sex, diagnosis and duration of rheumatic disease, type of TNF antagonist, and concomitant treatment. Type of CAE was classified as local or systemic cutaneous manifestation related to treatment administration (infusion reaction), infection, malignancy, or autoimmune skin disease. Time of onset of CAE and outcome were also recorded. The IRs of CAE per 1,000 patient‐years of exposure with 95% confidence intervals (95% CIs) were estimated. Multivariable analysis was performed to identify potential risk factors for CAE.
Results
A total of 5,437 patients were included, representing 17,330 patient‐years of exposure. A total of 920 CAE were reported; the IRs per 1,000 patient‐years were 53 (95% CI 50–57) for CAE, 28 (95% CI 25–30) for infection, 15 (95% CI 13–17) for infusion reactions, 5 (95% CI 4–6) for autoimmune skin diseases, and 3 (95% CI 2–4) for skin malignancy. The mean time between starting TNF antagonist treatment and CAE was 1.78 years. In 32% of patients, CAE required TNF antagonist withdrawal. The main risk factors for CAE were female sex and treatment with infliximab, leflunomide, and glucocorticoids.
Conclusion
The IR of CAE in patients treated with TNF antagonists is significant and should be addressed carefully, and withdrawal of therapy is required in some cases.
Introduction This study aims to describe the clinical characteristics, disease activity, and structural damage in patients with axial spondyloarthritis (axSpA) who receive chronic treatment with ...nonsteroideal anti-inflammatory drugs (NSAIDs) or advanced therapies in a clinical setting. Methods Cross-sectional study on axSpA patients consecutively recruited from the outpatient clinic of a tertiary hospital. We collected data on clinical and demographic characteristics, as well as treatment patterns involving NSAIDs and advanced therapies. Structural damage was assessed using mSASSS. Results Overall, data from 193 axSpA patients (83% ankylosing spondylitis) were gathered, with a mean disease duration of 21.4 years. Of these, 85 patients (44%) were exclusively taking NSAIDs, while 108 (56%) were receiving advanced therapies, with TNF inhibitors being the predominant choice (93 out of 108, 86.1%). Among patients using NSAIDs, 64.7% followed an on-demand dosing regimen, while only 17.6% used full doses. Disease activity was low, with a mean BASDAI of 3.1 and a mean ASDAS-CRP of 1.8. In comparison to patients under chronic NSAID treatment, those taking advanced therapies were primarily male (69.4% versus 51.8%, p = 0.025) and significantly younger (mean age of 49 versus 53.9 years, p = 0.033). Additionally, patients on advanced therapies exhibited lower ASDAS-CRP ( p = 0.046), although CRP serum levels and BASDAI scores did not differ between the two groups. In the multivariable analysis, therapy (NSAID versus biological treatment) was not independently associated with ASDAS-CRP, BASDAI or mSASSS. Conclusion This cross-sectional analysis of a real-world cohort of axSpA patients shows positive clinical and radiological outcomes for both NSAIDs and advanced therapies.
Parasitic infections may induce variable immunomodulatory effects and control of autoimmune disease.
Toxoplasma gondii
(
T. gondii
) is a ubiquitous intracellular protozoan that was recently ...associated with autoimmunity. This study was undertaken to investigate the seroprevalence and clinical correlation of anti-
T. gondii
antibodies in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We evaluated sera from European patients with RA (
n
= 125) and SLE (
n
= 164) for the prevalence of anti-
T. gondii
IgG antibodies (ATXAb), as well as other common infections such as Cytomegalovirus, Epstein-Barr, and Rubella virus. The rates of seropositivity were determined utilizing the LIAISON chemiluminescent immunoassays (DiaSorin, Italy). Our results showed a higher seroprevalence of ATXAb in RA patients, as compared with SLE patients 63 vs. 36 %, respectively (
p
= 0.01). The rates of seropositivity of IgG against other infectious agents were comparable between RA and SLE patients. ATXAb-seropositivity was associated with older age of RA patients, although it did not correlate with RA disease activity and other manifestations of the disease. In conclusion, our data suggest a possible link between exposure to
T. gondii
infection and RA.
Evidence suggests that citrullinated fibrin(ogen) may be a potential in vivo target of anticitrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis (RA). We compared the diagnostic ...yield of three enzyme-linked immunosorbent assay (ELISA) tests by using chimeric fibrin/filaggrin citrullinated synthetic peptides (CFFCP1, CFFCP2, CFFCP3) with a commercial CCP2-based test in RA and analyzed their prognostic values in early RA.
Samples from 307 blood donors and patients with RA (322), psoriatic arthritis (133), systemic lupus erythematosus (119), and hepatitis C infection (84) were assayed by using CFFCP- and CCP2-based tests. Autoantibodies also were analyzed at baseline and during a 2-year follow-up in 98 early RA patients to determine their prognostic value.
With cutoffs giving 98% specificity for RA versus blood donors, the sensitivity was 72.1% for CFFCP1, 78.0% for CFFCP2, 71.4% for CFFCP3, and 73.9% for CCP2, with positive predictive values greater than 97% in all cases. CFFCP sensitivity in RA increased to 80.4% without losing specificity when positivity was considered as any positive anti-CFFCP status. Specificity of the three CFFCP tests versus other rheumatic populations was high (> 90%) and similar to those for the CCP2. In early RA, CFFCP1 best identified patients with a poor radiographic outcome. Radiographic progression was faster in the small subgroup of CCP2-negative and CFFCP1-positive patients than in those negative for both autoantibodies. CFFCP antibodies decreased after 1 year, but without any correlation with changes in disease activity.
CFFCP-based assays are highly sensitive and specific for RA. Early RA patients with anti-CFFCP1 antibodies, including CCP2-negative patients, show greater radiographic progression.
Psoriatic arthritis (PsA) is an autoantibody-negative immune-mediated disease in which synovial lymphoid neogenesis (LN) occurs. We determined whether LN is associated with specific patterns of ...inflammatory cytokine expression in paired synovial tissue (ST) and fluid (SF) samples and their potential correlation with the clinical characteristics of PsA.
ST and paired SF samples were obtained from the inflamed knee of PsA patients. ST samples were immunostained with CD3 (T cell), CD20 (B cell), and MECA-79 (high endothelial vessels). Total ST mRNA was extracted, and the gene expression of 21 T-cell-derived and proinflammatory cytokines were measured with quantitative real-time PCR. SF concentrations of Th1, Th2, Th17, and proinflammatory cytokines were determined with the Quantibody Human Th17 Array. Clinical and biologic data were collected at inclusion and after a median of 27 months of follow-up.
Twenty (43.5%) of 46 patients had LN. Only two genes showed differences (Wilcoxon test, P < 0.06) in ST between LN-positive and LN-negative patients: interleukin-23A (IL-23A) (P = 0.058) and transforming growth factor-beta (TGF-β1) (P = 0.050). IL-23A expression was higher, and TGF-β1 expression was lower in LN-positive patients. ST IL-15 mRNA showed a nonsignificant trend toward higher expression in LN-positive patients, and SF IL-15 protein levels were significantly higher in LN-positive patients (P = 0.002). In all PsA patients, IL-23A mRNA expression correlated with C-reactive protein (CRP) (r = 0.471; P = 0.001) and swollen-joint count (SJC) (r = 0.350; P = 0.018), whereas SF levels of IL-6 and CC chemokine-ligand 20 (CCL-20) correlated with CRP levels (r = 0.377; P = 0.014 and r = 0.501; P < 0.0001, respectively).
These findings suggest differences in the cytokine profile of PsA patients with LN, with a higher expression of IL-23A and IL-15 and a lower expression of TGF-β1. In the entire group of patients, IL-23 ST expression and CCL20 SF levels strongly correlated with markers of disease activity. This cytokine pattern was not accompanied by gross clinical or biologic differences between LN-positive and -negative patients. Taken together, these results suggest a role of the IL-17/IL-23 cytokine axis in synovial LN in PsA.
Therapy with TNF blockers may induce cutaneous adverse events, but the development of morphea, a localized scleroderma lesion, is extremely infrequent. We describe a 37-year-old man with ankylosing ...spondylitis treated with adalimumab who developed morphea lesions in the lower limbs after 12 months of treatment. Adalimumab was discontinued, which resulted in progressive improvement in the skin lesions, with only mild hyperpigmentation remaining. We also review reports of morphea and other adverse cutaneous events related to anti-TNF treatment.
PDF
