Insufficient PD-1 expression during active autoimmune responses: a deep single-cell proteomics analysis in inflammatory arthritis.

Objectives: Programmed cell death protein-1 (PD-1) maintains peripheral immune tolerance by preventing T cell continuous activation. Aiming to understand the extent of PD-1 expression in inflammatory arthritis beyond its involvement with T cells, we assess its presence on various circulating single cells. Methods: Mass cytometry analysis of patients with active seropositive/seronegative rheumatoid (RA; n=9/8) and psoriatic (PsA; n=9) arthritis versus healthy controls (HC; n=13), re-evaluating patients after 3 months of anti-rheumatic treatment. Results: PD-1 was expressed in all leukocyte subpopulations, with the highest PD-1+ cell frequencies in eosinophils (59-73%) and T cells (50-60%), and the lowest in natural-killer cells (1-3%). PD-1+ cell frequencies and PD-1 median expression were comparable between patient subgroups and HC, in the majority of cell subsets. Exceptions included increases in certain T cell/B cell subsets of seropositive RA and specific monocyte subsets and dendritic cells of PsA; an expanded PD-1+CD4+CD45RA+CD27+CD28+ T subset, denoting exhausted T cells, was common across patient subgroups. Strikingly, significant inverse correlations between individual biomarkers of systemic inflammation (ESR and/or serum CRP) and PD-1+ cell frequencies and/or median expression were evident in several innate and adaptive immunity cell subsets of RA and PsA patients. Furthermore, all inverse correlations noted in individuals with active arthritis were no longer discernible in those who attained remission/low disease activity post-treatment. Conclusion: PD-1 expression may be insufficient, relative to the magnitude of the concomitant systemic inflammatory response on distinct leukocyte subsets, varying between RA and PsA. Our results point to the potential therapeutic benefits of pharmacological PD-1 activation, to rebalance the autoimmune response and reduce inflammation.

New-Onset MDA-5 Dermatomyositis in a Patient Following COVID-19 Vaccination: A Case Report.

Vaccination against Sars-CoV-2 has been proven to significantly reduce COVID-19 morbidity and mortality and is therefore recommended for the general population, and especially for seniors with impaired immunity. However, it is currently postulated that COVID-19 vaccines could rarely induce autoimmune diseases in previously healthy individuals. We report a case of new-onset anti-melanoma differentiation-associated protein 5 (anti-MDA5) antibody-positive dermatomyositis in a patient presenting with rash and fever following the third dose of COVID-19 vaccine. The laboratory testing revealed high titres of anti-MDA-5 antibody and chest computed tomography showed micronodular lesions and ground glass opacities bilaterally. The patient was promptly treated with corticosteroids, methotrexate, and azathioprine, and was later started on rituximab due to dermatomyositis rash exacerbation along with newly formed, diffuse skin ulcers. Our case highlights the potential immunogenicity of COVID-19 vaccines and the need for further reporting of rare rheumatic syndromes possibly related to COVID-19 disease and vaccination.

Selective JAK-Inhibitors in Spondyloarthritis.

As our research interest and knowledge increases in the field of Spondyloarthritis, new aspects also emerge as regards to their therapeutic approach. JAK inhibitors (JAKi) are a relatively new treatment option, aiming molecules in the JAK-STAT pathway, which has a leading role in the pathophysiology of both Psoriatic Arthritis and Axial Spondyloarthritis. JAKi exhibit different selectivity towards the four different members of the JAK family (namely JAK1, JAK2, JAK3, and TYK2), possibly reflecting different efficacy and safety profile. Although knowledge is more consolidated for rheumatoid arthritis in which JAKi are being used for more than 10 years, data are still accumulating for PsA/SpA. In this review we aim to present and assess current knowledge about the efficacy of JAKi (with a focus on selective JAKi) in the treatment of patients with SpA and evaluate their safety profile as some concerns may arise around this therapeutic option.

Identification and characteristics of patients with potential difficult-to-treat Psoriatic Arthritis: exploratory analyses of the Greek PsA registry.

OBJECTIVE: To present the characteristics of patients with potential difficult-to-treat (D2T) psoriatic arthritis (PsA). METHODS: We used data from the Greek multicentre registry of PsA patients. D2T-PsA was defined as follows: patients with at least 6-months disease duration, who have failed to at least 1 csDMARD and at least 2 bDMARDs/tsDMARDs with a different mechanism of action and have either at least moderate disease activity (MODA) defined as DAPSA > 14, and/or are not at minimal disease activity (MDA). Demographic and clinical characteristics were compared between D2T and non-D2T PsA patients. In two sensitivity analyses, patients classified as D2T solely according to the MODA or MDA criterion were examined separately. RESULTS: Among 467 patients included, 77 (16.5%) were considered D2T and 390 non-D2T PsA. Compared with non-D2T, patients with D2T PsA presented more commonly with extensive psoriasis (p< 0.0001) and were more likely to have higher BMI (p= 0.023) and a history of inflammatory bowel disease (p= 0.026). In the MODA and MDA sensitivity analyses, 7.5% and 12.5% of patients were considered D2T, respectively. In both sensitivity analyses, extensive psoriasis was again identified as an independent variable for D2T PsA (p= 0.001 and p= 0.008, respectively). Moreover, female gender (p= 0.034) in the MODA analysis and axial disease (p= 0.040) in the MDA analysis were independent variables for D2T PsA. CONCLUSION: Despite the availability of therapies, D2T PsA is common in real-life cohorts of patients with PsA and extensive psoriasis. High BMI, female gender, axial-disease, and history of IBD were also associated with D2T PsA.

Outcomes of COVID-19 re-infections: a single-center cohort of 167 patients with systemic rheumatic diseases.

Data on COVID-19 re-infections in patients with systemic rheumatic diseases (SRDs) are lacking. We aimed to describe the course and outcomes of COVID-19 re-infections in these patients versus controls. In this single-center retrospective study, we included 167 consecutive SRD patients with at least one COVID-19 re-infection (mean age 47.3 years, females 70.7%). SRD patients were compared in terms of patient-perceived COVID-19 re-infection severity and hospitalizations/deaths with 167 age/sex-matched non-SRD controls. Logistic regression analysis was performed to assess potential milder re-infection versus primary infection severity, adjusting for study group, demographics (age, sex), vaccination status, body mass index, smoking, and comorbidities. 23 and 7 out of 167 re-infected SRD patients experienced two and three re-infections, respectively, which were comparable to the re-infection rates in controls (two: 32; and three: 2) who also had comparable COVID-19 vaccination history (89% and 95% vaccinated, respectively). In the initial infection, patients with SRDs were hospitalized (7.2% versus 1.8%, p = 0.017), and had received antiviral treatment (16.1% versus 4.7%, p < 0.001) more frequently than controls. However, hospitalizations (1.8% vs 0.6%) and antiviral treatment (7.8% vs 3.5%) did not differ (p > 0.05) between patients and controls at the first re-infection, as well as during the second and third re-infection; no deaths were recorded. Perceived severity of re-infections was also comparable between patients and controls (p = 0.847) and among those on biologic DMARDs or not (p = 0.482). In multivariable analysis, neither SRDs presence nor demographics or comorbidities were associated with COVID-19 re-infection severity. COVID-19 re-infection severity (patient-perceived/hospitalizations/deaths) did not differ between SRDs and controls.

Progression of subclinical atherosclerosis in ankylosing spondylitis: a 10-year prospective study.

Chronic systemic inflammation contributes to increased CVD burden in Ankylosing Spondylitis (AS). Since long-term follow-up data on subclinical atherosclerosis acceleration are lacking, we examined its progression in contemporary AS patients during 10 years. Fifty-three (89% male, aged 50.4 (36.3-55.9) years,) non-diabetic, CVD-free AS patients and 53 age-sex-matched non-diabetic, control individuals were re-evaluated after 9.2-10.2 years by ultrasonography for carotid/femoral atheromatosis, pulse wave velocity (PWV) and intima-media thickness (IMT), performed by the same operator/protocol. New atheromatic plaque formation, PWV deterioration, and IMT increase were associated only with classical CVD risk factors, as reflected by the heartSCORE (age, gender, smoking status, blood pressure and cholesterol levels) by multivariate analysis, rather than disease presence. However, among AS patients, despite remission/low disease activity at follow-up end in 79%, atheromatosis progression was associated by multivariate analysis with higher BASDAI scores (p = 0.028), independently of biologic therapies administered in 2/3 of them. Moreover, in AS patients, but not in controls, PWV values at baseline were associated with plaque progression during the 10-year follow-up after taking into account baseline heartSCORE and plaque burden status (p = 0.033). Despite comparable prevalence of both hypertension and hypercholesterolemia at baseline between patients and controls, a lower percentage of AS patients had achieved "adequate" CVD risk factor control at follow-up end (11% vs 25% respectively, p = 0.076). Classical CVD risk factors and residual disease activity account for the progression of subclinical atherosclerosis in AS, pointing to the unmet needs in the contemporary management of these patients.

Type-I interferon pathway and DNA damage accumulation in peripheral blood of patients with psoriatic arthritis.

Objectives: The abnormal DNA damage response is associated with upregulation of the type-1 interferon (IFN-I) pathway in certain rheumatic diseases. We investigated whether such aberrant mechanisms operate in psoriatic arthritis (PsA). Methods: DNA damage levels were measured by alkaline comet assay in peripheral blood mononuclear cells from 52 PsA patients and age-sex-matched healthy individuals. RNA expression of IFIT1, MX1 and IFI44, which are selectively induced by IFN-I, was quantitated by real-time polymerase chain reaction and their composite normalized expression resulted in IFN-I score calculation. RNA expression of IL1ß, IL6, TNF, IL17A and IL23A was also assessed in PsA and control subgroups. Results: In PsA, DNA damage accumulation was increased by almost two-fold compared to healthy individuals (olive tail moment arbitrary units, mean ± SD; 9.42 ± 2.71 vs 4.88 ± 1.98, p<0.0001). DNA damage levels significantly correlated with serum C-Reactive-protein and IL6 RNA expression in PBMCs. Despite increased DNA damage, the IFN-I score was strikingly lower in PsA patients compared to controls (-0.49 ± 6.99 vs 4.24 ± 4.26; p<0.0001). No correlation was found between IFN-I pathway downregulation and DNA damage. However, the IFN-I score in a PsA subgroup was lower in those patients with higher IL1ß expression, as well as in those with higher TNF/IL23A PBMCs expression. Conclusion: DNA damage in PsA correlates with measures of inflammation but is not associated with the IFN-I pathway induction. The unexpected IFN-I downregulation, albeit reminiscent to findings in experimental models of spondyloarthritis, may be implicated in PsA pathogenesis and explained by operation of other cytokines.

Higher frequency but similar recurrence rate of uveitis episodes in axial spondylarthritis compared to psoriatic arthritis. A multicentre retrospective study.

BACKGROUND/OBJECTIVE: Data on risk factors predicting uveitis development in spondyloarthritis (SpA) is scarce. Our aim was to examine associations between demographic, clinical and/or laboratory characteristics of SpA with the occurrence and the course of uveitis, including ocular damage and recurrence rate. METHODS: Characteristics (at disease diagnosis and ever-present) from axSpA and Psoriatic arthritis (PsA) patients followed in 3 tertiary rheumatology-clinics were retrospectively recorded. Comparisons were made between patients with and without uveitis, as well as between those with uveitis-rate [episodes/year] above the median uveitis-rate in the whole cohort ("recurrent"-uveitis) and the remaining uveitis patients ("non-recurrent uveitis"). In multivariable models, age, gender and variables significantly different in univariate analyses were included. RESULTS: 264 axSpA and 369 PsA patients were enrolled. In axSpA, uveitis occurred in 11.7% and was associated with HLA-B27 (OR = 4.15, 95%CI 1.16-14.80, p = 0.028) and ever-present peripheral arthritis (OR = 3.05 (1.10-8.41, p = 0.031). In contrast, uveitis in PsA occurred only in 2.7% of patients and was associated with SpA family-history (OR = 6.35 (1.29-31.27), p = 0.023) axial disease at diagnosis (OR = 5.61 [1.01-28.69], p = 0.038) and disease duration (OR = 1.12 [1.04-1.21], p = 0.004). Median uveitis recurrence rate was comparable between axSpA and PsA (0.205 and 0.285 episodes/year, respectively). No associations were found between recurrent uveitis and demographic/clinical/laboratory characteristics. Ocular damage (e.g. synechiae) was seen in 16.1% of axSpA and 30% of PsA patients, all of them with recurrent uveitis. CONCLUSION: Uveitis occurred more commonly in axSpA than in PsA patients, while uveitis recurrence rate was similar. Permanent ocular damage may occur more often in PsA than axSpA.

Distinct innate and adaptive immunity phenotypic profile at the circulating single-cell level in Psoriatic Arthritis.

Mass cytometry was employed to investigate 47 circulating leukocyte subsets in patients with active psoriatic arthritis (PsA, n = 16) compared to healthy controls (n = 13), seropositive (RF and/or anti-CCP, n = 12) and seronegative (n = 9) RA patients. Comparing PsA to controls, different cell frequencies were found in both innate and adaptive immunity cell subsets, as well as in cells bridging innate and adaptive immunity. In some T cell subsets increased costimulatory molecules' expression in PsA, was also noted.No changes were observed in patients who remained disease-active after 3 months of treatment, in contrast to those who achieved remission/low-disease activity. Comparing PsA to seropositive RA, elevated frequencies of naïve and activated CD8+ T cells, B cells, MAIT/iNKT and ILCs were found, while the opposite was the case for terminal effector, senescent, and Th2-like cells. Strikingly, the composition of the leukocyte pool in PsA was comparable to seronegative RA, providing evidence for the pathogenetic similarities between these two entities.

Effect of body mass index on treatment response of biologic/targeted-synthetic DMARDs in patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis. A systematic review.

BACKGROUND: Overweight and/or obese patients with inflammatory arthritis (IA) have higher disease activity and lower chances of achieving and/or maintaining the treatment targets. Weight/obesity also appears to negatively affect the response to tumor necrosis factor (TNF) inhibitors in IA patients, including rheumatoid arthritis -RA, psoriatic arthritis -PsA, axial spondyloarthritis -AxSpA. We conducted a systematic literature review (SLR) for the effect of weight/body-mass-index (BMI) in the efficacy of all approved biologic (b) and targeted-synthetic (ts) DMARDs for the treatment of IA. METHODS: For this PROSPERO-registered SLR, we searched PubMed, Scopus and Cohrane-Library from inception up to June 21st 2022. Clinical-trials (randomized and non-randomized) and observational studies of RA, PsA or AxSpA patients that reported the effect of weight/BMI on response (all possible outcomes) to b/ts-DMARDs were included. Risk-of-bias was assessed via RoB2-Cochrane-tool and Newcastle-Ottawa-scale for randomized and non-randomized studies, respectively. FINDINGS: Out of 996 references, 75 eventually fulfilled the inclusion criteria (of which 10 studies were retrieved through manual-search). Among the included studies (TNF-inhibitors: 34, IL-12/23 inhibitors: 4, IL-23 inhibitor: 1, IL-17 inhibitors: 7, tocilizumab: 18, abatacept: 8, rituximab: 3, JAK-inhibitors: 5), most had medium RoB. Efficacy of TNF-inhibitors was affected by BMI in all forms of IA. Data are not robust to compare the effect among various TNF-inhibitors. In contrast, favorable results of IL-23 and IL-17 inhibitors did not appear to be influenced by increased BMI in PsA or AxSpA patients. Similar evidence exists for tocilizumab (in RA) and for abatacept (in RA and PsA), while no conclusion can be drawn for rituximab. More data are needed for JAK-inhibitors, although the effect of weight/BMI does not seem to be significant so far. INTERPRETATION: Weight/BMI should be considered in the treatment-plan of IA patients, with its effect being more pronounced for TNF-inhibitors compared to other b/ts-DMARDs.

Musculoskeletal Complications of Celiac Disease: A Case-Based Review.

Primary diagnosis of celiac disease (CD) in rheumatology department is not common in daily clinical practice, due to the fact that diarrhoea is usually the dominant symptom. Extra-intestinal manifestations, such as arthralgia, myalgia, osteomalacia, and osteoporosis are not rare in these patients. We present a case of a 66-year-old man, who came to the outpatient rheumatology clinic, complaining of back and knee pain. Osteopenia was observed in plain radiographs, whereas extensive laboratory testing revealed celiac disease, vitamin D deficiency, and extremely low bone mineral density (BMD) due to osteomalacia. Gluten-free diet (GFD) initiation and administration of vitamin D and calcium supplements resulted in significant symptom and BMD improvement over 6 months. A significant proportion of CD patients might present with arthralgia, arthritis, back pain, myalgia, or bone pain. Importantly, up to 75% of patients might have reduced BMD, due to osteoporosis or osteomalacia, while they also carry a significant risk for fracture. However, the introduction of GFD and calcium/vitamin D supplementation significantly ameliorates symptoms and BMD in most cases. Increased awareness of CD's musculoskeletal manifestations by rheumatologists is important for early recognition and management of this condition and its complications.

Late-Onset Psoriatic Arthritis: Are There Any Distinct Characteristics? A Retrospective Cohort Data Analysis.

As life expectancy increases, psoriatic arthritis (PsA) in older individuals becomes more prevalent. We explored whether late-onset versus earlier-onset PsA patients display different clinical features at diagnosis and/or during the disease course, as well as different treatment approaches and comorbidity profiles. We retrospectively collected data from consecutive PsA patients attending two rheumatology centers (December 2017-December 2022). Late-onset PsA patients (diagnosis-age: ≥60 years) were compared to those diagnosed before 60 years old. Univariate analyses and logistic regression were performed to examine for factors associated with late-onset PsA. For sensitivity analyses, the cohort's mean diagnosis age was used as the cut-off value. Overall, 281 PsA patients were included (mean ± SD diagnosis-age: 46.0 ± 13.3 years). Of them, 14.2% (N = 40) had late-onset PsA. At diagnosis, after controlling for confounders, no demographic and clinical differences were identified. During the disease course, the late-onset group exhibited 65% fewer odds of manifesting enthesitis (adjusted Odds-ratio-adOR 0.35; 95% confidence interval 0.13-0.97), but higher frequency of dyslipidemia (adOR 3.01; 1.30-6.95) and of major adverse cardiovascular events (adOR 4.30; 1.42-12.98) compared to earlier-onset PsA group. No differences were found in the treatment approaches. In sensitivity analyses, PsA patients diagnosed after 46 (vs. ≤46) years old had an increased frequency of hypertension (adOR 3.18; 1.70-5.94) and dyslipidemia (adOR 2.17; 1.25-3.74). The present study underpins that late-onset PsA is not uncommon, while the age at PsA onset may affect the longitudinal clinical expression of the disease. Patients with late-onset PsA were less likely to manifest enthesitis but displayed increased cardiovascular risk.

Ixekizumab therapy following secukinumab inadequate response in psoriatic arthritis: a case series focusing on axial disease.

There are limited data regarding cycling between interleukin-17 (IL-17) inhibitors in psoriatic arthritis (PsA). We aimed to report the efficacy of an IL-17 inhibitor (ixekizumab-IXE) after inadequate response (IR) of another one (secukinumab-SEC) in patients with PsA. Case series of PsA patients who received IXE after SEC-IR in four rheumatology centers between 1/9/2021 and 1/9/2022 were included. Peripheral arthritis was assessed with disease activity in psoriatic arthritis score (DAPSA) and skin involvement with body surface area (BSA). Axial disease was defined as having both imaging and clinical features and its activity was measured with the ankylosing spondylitis disease activity score (ASDAS). Twenty-four patients (54.2% female, mean [SD] age: 51.6 [14.1]) who were SEC-IR and received IXE either immediately (n = 11) or after ≥ 1 interposed biologic disease modifying anti-rheumatic drug (bDMARD) (n = 13) were included. Patients were followed on IXE for a mean [SD] period of 9.6 [4.9] months. Among patients with peripheral arthritis (n = 24), the mean [SD] DAPSA decreased from 22.8 [8.6] to 13.6 [7.8] during follow-up (p = 0.0001) with 62.5% of patients showing improvement in the DAPSA disease activity categories. For patients with axial involvement (n = 16), a clinically meaningful improvement (Δ ≥ 1.1 in ASDAS) was noted in 50% (8/16), while dactylitis and enthesitis resolution was observed in 60% (3/5) and 83% (5/6) of patients, respectively. Regarding psoriasis, the mean [SD] BSA of involved skin decreased from 8.7 [8.7] to 2.4 [3.3] (p = 0.001). In this case series, treatment with IXE after inadequate response to another IL-17 inhibitor (SEC) was efficacious in a real-world setting in patients with PsA, including axial disease.

Comorbidities in Psoriatic Arthritis: A Narrative Review.

PURPOSE: Psoriatic arthritis (PsA) is a common type of inflammatory arthritis. Patients with PsA present with certain extra-articular manifestations and comorbidities (often collectively called psoriatic disease). The purpose of the present review was to highlight the main comorbidities in the setting of PsA. METHODS: A narrative review was performed using data from articles found in a search of PubMed and Scopus using the terms psoriatic arthritis and comorbidities. FINDINGS: Cardiovascular disease (CVD), as well as metabolic and mental health disorders, are the most common comorbidities in patients with PsA. In most cases, underlying inflammation seems to be involved in the increased risk for CVD in PsA, while a bidirectional relationship seems to operate between mental health disorders and psoriatic disease. The treatment of patients with PsA, especially with biologic disease-modifying antirheumatic drugs, has been shown to lead to favorable outcomes regarding the CVD risk. However, it is debatable whether specific drug classes are more effective than others or should be avoided in patients with CVD risk factors. Comorbidity of mental health disorders is even more complex, given the difficulties in measuring and reporting these comorbidities in clinical trials and in clinical practice. IMPLICATIONS: Future studies are needed for a better understanding of the pathogenic mechanisms of, and the development of better protocols for the identification and treatment of patients with, comorbidities in patients with PsA. The education of clinicians, health care professionals in rheumatology, and patients could be useful in achieving this goal.

Depression and anxiety in a real-world psoriatic arthritis longitudinal study: should we focus more on patients' perception?

OBJECTIVES: Longitudinal studies using validated tools to evaluate depression and anxiety in psoriatic arthritis (PsA) are lacking. We aimed to estimate their course in PsA and to examine possible associations with disease-related parameters and patient-reported outcomes (PROs). METHODS: PsA patients attending two outpatient rheumatology clinics were consecutively enrolled (January 2019-June 2021, n=128). The hospital anxiety and depression scale (HADS) was used at two sequential visits (mean±SD: 10±6 months) to prospectively assess depression (HADS-Depression) and anxiety (HADS-Anxiety) (cut-off scores ≥11). Associations with demographic, clinical, laboratory features and PROs for quality of life (QoL) (EQ-5D), functional status (HAQ-DI) and nocebo-behaviour (Q-No) were examined. 'Change' was the difference between values at the first and second visit. RESULTS: Prevalence of depression and anxiety at the first visit was 19.5% and 21.1%, respectively. Depression was associated with EQ-5D [OR (95% CI): 1.70 (1.02-2.59), p=0.019] and anxiety with EQ-5D [1.81 (1.20 to 2.72), p=0.005], nocebo-behaviour [1.19 (1.01-1.40), p=0.04] and current corticosteroid use [6.95 (1.75-27.59), p=0.006]. At the second visit, HADS-Depression and HADS-Anxiety scores were improved in 40.9% and 41.9% of patients, respectively. While no associations were found for HADS-Anxiety score change, changes in HADS-Depression score correlated with changes in subjective (tender joint count, r= 0.204, p=0.049; PtG, r= 0.236, p=0.023; patient pain assessment, r= 0.266, p=0.01) but not objective (swollen joint count, ESR, CRP) parameters of disease activity. CONCLUSIONS: In PsA, depression and anxiety are associated with worse PROs, including QoL. Subjective parameters of disease activity parallel course of depression.

Different COVID-19 outcomes among systemic rheumatic diseases: a nation-wide cohort study.

OBJECTIVES: To investigate coronavirus disease 2019 (COVID-19)-associated risk of hospitalization and death in RA, AS, PsA, SLE and SSc in comparison with the general population during the first year of the pandemic, and compare their overall mortality with 2019. METHODS: Interlinking nationwide electronic registries, we recorded confirmed COVID-19-associated infections, hospitalizations and deaths, and all-cause deaths between 1 March 2020 and 28 February 2021 in all adults with RA, AS, PsA, SLE and SSc under treatment (n = 74 970, median age 67.5, 51.2, 58.1, 56.2 and 62.2 years, respectively) and in random comparators from the general population matched (1:5) on age, sex and region of domicile. Deaths from all causes during 2019 were also recorded. RESULTS: Compared with the general population, incidence rates (IR) for COVID-19-associated hospitalization were higher in RA [IR ratio (IRR) 1.71(1.50-1.95)], SLE [2.0 (1.4-2.7)] and SSc [2.28 (1.29-3.90)], while COVID-19-associated death rates were higher in RA [1.91 (1.46-2.49)]. When focusing only on severe acute respiratory syndrome coronavirus 2-infected subjects, after adjusting for age and gender, the odds ratio for COVID-19 associated death was higher in RA [1.47 (1.11-1.94)] and SSc [2.92 (1.07-7.99)] compared with the general population. The all-cause mortality rate compared with the general population increased in RA during the first year of the pandemic (IRR 0.71) with reference to 2019 (0.59), and decreased in SSc (IRR 1.94 vs 4.36). CONCLUSION: COVID-19 may have a more severe impact in patients with systemic rheumatic disease than in the general population. COVID-19-related mortality is increased in subgroups of patients with specific rheumatic diseases, underscoring the need for priority vaccination and access to targeted treatments.

Disease Profile and Achievement of Therapeutic Goals in a Modern, Nationwide Cohort of 923 Patients with Psoriatic Arthritis.

Background: Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease affecting skin, joints, entheses, and spine with various extra-musculoskeletal manifestations and comorbidities. The reported patient, disease and treatment characteristics in the modern therapeutic era are limited. Methods: In this cross-sectional, multi-centre, nationwide study, we recorded the demographic, clinical, and therapeutic characteristics as well as the comorbidities of patients with PsA seen for 1 year (1/1/2022-31/12/2022). Results: 923 patients (55% females) with a median (IQR) age of 57 (48-65) years and a mean disease duration of 9.5 years were enrolled. Family history of psoriasis and PsA was noted in 28.3% and 6.3%, respectively. Most patients had limited psoriasis (BSA<3: 83%) while enthesitis, dactylitis, nail and axial involvement reported in 48.3%, 33.2%, 43% and 25.9% of patients, respectively. Regarding comorbidities, approximately half of patients had dyslipidaemia (42%) or hypertension (45.4%), 36.8% were obese and 17% had diabetes while 22.7% had a depressive disorder. Overall, 60.1% received biologics and among them more patients treated with anti-IL-17 or -12/23 agents were on monotherapy (64.2%) compared to those on TNFi monotherapy (49.4%, p=0.0001). The median PsA activity as assessed by the DAPSA score was 6 (IQR: 2.3 - 13.1) with 46% of patients reaching minimal disease activity status (MDA). Conclusion: In this large, real life, modern cohort of patients with PsA with frequent comorbidities who were treated mainly with biologics, almost half achieved minimal disease activity. These results show the value of existing therapeutic approaches while at the same time highlight the existing unmet needs.

Normal C-reactive protein in active psoriatic arthritis: results from real-world clinical practice.

Background: The value of normal C-reactive protein (CRP) in psoriatic arthritis (PsA) is debatable. Objectives: To test the hypothesis that CRP is frequently normal in contemporary real-world PsA patients, despite active disease. Design: In this cross-sectional study, patients were divided into two groups: CRP ⩽ 0.5 mg/dl (normal) and CRP > 0.5 mg/dl (increased). Having as dependent variable the CRP status, these groups were compared for disease-related features, including composite disease activity indices [clinical Disease Activity in PSoriatic Arthritis (cDAPSA) and minimal disease activity (MDA)] and patient-reported outcomes (PROs). Agreement between CRP status and cDAPSA/MDA scores was calculated (Cohen's kappa). Methods: Data from consecutive PsA patients attending two outpatient rheumatology clinics (January 2019-June 2021) were analysed. Results: From 128 patients enrolled (51.6% females; mean ± standard deviation age: 53.4 ± 11.7 years; 23.4%, 48.4% and 64.1% treated with glucocorticoids, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biologic DMARDs, respectively), two-thirds (66.4%, n = 85) had normal CRP values. CRP status was not associated with any of the disease-related parameters and PROs, but only with ESR [odds ratio: 1.04 (95% confidence interval: 1.01-1.06), p = 0.005]. Among patients with normal CRP, 45.9% (39/85) were on non-MDA state, while 21.2% (18/85) had cDAPSA-moderate and 5.9% (5/85) had cDAPSA-high disease activities. Conversely, 54.2% (39/72) of patients on non-MDA state and 52.3% (23/44) of those with cDAPSA-moderate or cDAPSA-high disease activity had normal CRP values. Cohen's kappa between normal CRP and MDA, cDAPSA-remission, and cDAPSA-remission/low disease activity was -0.26, -0.21 and -0.22, respectively, displaying total disagreement. Conclusion: Normal CRP in PsA should not be used as surrogate marker of remission or low/MDA, therefore needs to be interpreted with caution in clinical decision-making.

Choosing the Appropriate Target for the Treatment of Psoriatic Arthritis: TNFα, IL-17, IL-23 or JAK Inhibitors?

Psoriatic arthritis (PsA) is a highly heterogenous disease. Apart from arthritis and psoriasis, other manifestations can also occur, including enthesitis, dactylitis, axial-, nail-, eye- and bowel- involvement. Comorbidities are also frequent in the setting of PsA, with cardiovascular disease and mental-health disorders being the most frequent. The Rheumatologist's arsenal has many different treatment options for treating PsA. Despite their effectiveness, there are some differences in terms of efficacy and safety that might affect clinician's decision for one or the other drug. Comparing biologic DMARDs and JAK-inhibitors, one could say that they have similar effectiveness in terms of musculoskeletal manifestations. However, anti-IL-17 and anti-IL-23 drugs seem to be more effective for skin manifestations. In contrast, JAK-inhibitors and etanercept might be less effective for these manifestations. Inflammatory bowel disease and uveitis are non-responsive to etanercept and anti-IL-17 drugs. As regards to comorbidities, data are scarce, but future studies will shed light on possible differential effect of bDMARDs or JAK-inhibitors. Safety is always an important drive for choosing the appropriate treatment. Infections are the most common adverse event of these drugs. Etanercept and anti-IL-17 drugs are safer for patients having latent tuberculosis, while herpes zoster is more common in individuals receiving JAK-inhibitors. Finally, venous thromboembolism risk, should be taken into account when JAK-inhibitors are used. In this review, we comparatively present, as outlined above, the various aspects that could affect the choice of the appropriate bDMARD or JAK-inhibitor for the treatment of a PsA patient.

The role of IL-23 and the use of IL-23 inhibitors in psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterised by musculoskeletal and extra-articular manifestations, most notably psoriasis. While the underlying pathogenetic mechanisms are not yet fully understood, a central role has been identified for the IL-23/IL-17 pathway. OBJECTIVES: We briefly describe the role of IL-23 in the pathogenesis of PsA and go on to describe the available anti-IL-23 agents and their place in the management of PsA. METHODS: This is a narrative review of the current literature, focussing on the results of the phase 3 studies in PsA for the IL-12/23 p40 inhibitor ustekinumab and the more recent IL-23 p19 inhibitors guselkumab, risankizumab and tildrakizumab. RESULTS: IL-23 triggers expression of IL-17 and other effector cytokines in a variety of cells, leading to tissue inflammation and injury. Targeting IL-23, particularly with p19 inhibitors, appears to be an effective and safe strategy for multiple clinical domains in PsA, most notably the skin, with some differences in efficacy emerging between these agents. CONCLUSION: The development of IL-23 inhibitors represents a significant advance in the management of psoriatic disease. In the absence of head-to-head studies, future data emerging from real-world experiences of individual IL-23 p19 inhibitors will help inform the use of these agents in relation to other biologics in PsA.