Stress in patients with Juvenile Idiopathic Arthritis (JIA) has been found to be associated with orofacial pain, psychological distress, jaw dysfunction and loss of daily activities in a ...cross-sectional study. The aim of this study was to investigate the relations between stress and change of stress over time versus changes in orofacial pain, psychosocial factors and jaw function over a two-year period in patients with JIA.
This is a two-year prospective follow-up study involving 40 JIA patients. At baseline (2015) the median age was 12 years and at two-year follow up (2018) 14 years. The JIA patients were examined clinically and with questionnaires at baseline and follow-up with the diagnostic criteria for temporomandibular disorders (DC/TMD) and completed the same set of DC/TMD questionnaires regarding orofacial pain symptoms and psychosocial factors.
Change in stress was associated with change in catastrophizing, psychological distress as well as limitation in general function and jaw function.
This study emphasizes the importance of maintaining a low stress level in patients with JIA since an increase in stress level over a two-year period seems to impair jaw function as well as psychological distress and catastrophizing.
Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in ...circulating IC might be of prognostic value.
A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment.
High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers.
Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lupus erythematosus patients. Characterization of autoantibody content in circulating immune complexes could prove useful in treatment evaluation in systemic lupus erythematosus and other immune complex-associated diseases.
Impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on individuals with arthritis has been highlighted whereas data on other rheumatic diseases, e.g., systemic lupus ...erythematosus (SLE), are scarce. Similarly to SLE, severe SARS-CoV-2 infection includes risks for thromboembolism, an unbalanced type I interferon response, and complement activation. Herein, SARS-CoV-2 antibodies in longitudinal samples collected prior to vaccination were analyzed and compared with SLE progression and antinuclear antibody (ANA) levels.
One hundred patients (83 women) with established SLE and a regular visit to the rheumatologist (March 2020 to January 2021) were included. All subjects donated blood and had done likewise prior to the pandemic. SARS-CoV-2 antibody isotypes (IgG, IgA, IgM) to the cell receptor-binding S1-spike outer envelope protein were detected by ELISA, and their neutralizing capacity was investigated. IgG-ANA were measured by multiplex technology.
During the pandemic, 4% had PCR-confirmed infection but 36% showed SARS-CoV-2 antibodies of ≥1 isotype; IgA was the most common (30%), followed by IgM (9%) and IgG (8%). The antibodies had low neutralizing capacity and were detected also in prepandemic samples. Plasma albumin (
= 0.04) and anti-dsDNA (
= 0.003) levels were lower in patients with SARS-CoV-2 antibodies. Blood group, BMI, smoking habits, complement proteins, daily glucocorticoid dose, use of hydroxychloroquine, or self-reported coronavirus disease 2019 (COVID-19) symptoms (except fever, >38.5°C) did not associate with SARS-CoV-2 antibodies.
Our data from early 2021 indicate that a large proportion of Swedish SLE patients had serological signs of exposure to SARS-CoV-2 but apparently with a minor impact on the SLE course. Use of steroids and hydroxychloroquine showed no distinct effects, and self-reported COVID-19-related symptoms correlated poorly with all antibody isotypes.
We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 ...belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-α2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL;
= 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL;
= 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL;
= 0.003). Levels of anti-dsDNA (
< 0.001), anti-Smith antigen (Sm) (
= 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (
< 0.001), anti-Sm-U1RNP complex (
= 0.028), and anti-ribosomal P (
= 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29;
= 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-α2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.
Objectives: Recently, we demonstrated a negative impact of smoking on belimumab efficacy in patients with systemic lupus erythematosus (SLE). Here, we particularly investigated clinical effects of ...belimumab and a potential impact of smoking in mucocutaneous and articular SLE.
Methods: We surveyed 62 SLE patients treated between 2011 and 2017. Evaluation included the mucocutaneous descriptors of SLEDAI-2K (rash, alopecia, mucosal ulcers; mcSLEDAI-2K), CLASI, the arthritis SLEDAI-2K descriptor (arSLEDAI-2K) and the 28-joint count.
Results: mcSLEDAI-2K and CLASI activity decreased from baseline to month 6 and 12 (P < 0.001 for all). No worsening in CLASI damage was observed. Current or previous smokers displayed a higher probability of unchanged/worsened mcSLEDAI-2K compared to never smokers (OR: 6.4; 95% CI: 1.5-27.4; P = 0.012), also after adjustment for antimalarial agents. arSLEDAI-2K scores had decreased at month 6 (P < 0.001) and 12 (P < 0.001). Likewise, tender and swollen 28-joint counts had improved at month 6 (P = 0.010 and P < 0.001, respectively) and 12 (P = 0.001 for both). We observed no impact of smoking on belimumab efficacy in articular SLE.
Conclusion: We observed a negative impact of smoking on the efficacy of belimumab in mucocutaneous SLE. In contrast, no impact of smoking on belimumab efficacy was seen in patients with articular manifestations.
Anti-phospholipid syndrome (APS) and systemic lupus erythematous (SLE) are autoimmune disorders that often co-occur. Anti-phospholipid antibodies (aPL) are typical of both conditions and may be ...associated with vascular events and pregnancy-related morbidities. Whereas, aPL-screening is mandatory for individuals with suspected SLE, the clinical value of longitudinal aPL analyses in established SLE is unclear.
We investigated the occurrence and variation of IgG/IgA/IgM anti-cardiolipin (aCL) and anti-β2-glycoprotein-I (anti-β2GPI) antibodies, using both the manufacturer's cut-off and a cut-off based on the 99th percentile of 400 apparently healthy donors, in recent-onset SLE. Furthermore, we evaluated the relationships between aPL levels and SLE/APS manifestations, as well as the pharmacotherapy. Patients with SLE who met validated classification criteria were included in this prospective study (
= 54). Samples were obtained at 0, 6, 12, 24, 36, 48, 60, 72, 84, and 96 months after SLE diagnosis.
Depending on the cut-off applied, 61.1 or 44.4% showed a positive result for at least one aPL isotype or the lupus anticoagulant test over time. Median values for all six aPL isotypes numerically decreased from inclusion to last follow-up, but none of the isotypes met statistical significance. Seroconversion (from positive to negative, or the opposite direction) was occasionally seen for both aCL and anti-β2GPI. IgA and IgM anti-β2GPI were the most common isotypes, followed by IgM aCL. Presence of IgG aCL associated significantly with myocardial infarction and miscarriage, and IgG/IgA anti-β2GPI with miscarriage.
aPL were common during the first years of SLE. Even though the levels fluctuated over time, the patients tended to remain aPL positive or negative. Repeated aPL testing in the absence of new symptoms seems to be of uncertain value in patients with recent-onset SLE.
The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders ...continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates of neutrophil extracellular traps (NETs) occluding the affected vessels. Like COVID-19, systemic lupus erythematosus (SLE) is characterized by, amongst others, an increased risk of thromboembolism. An imbalance between NET formation and clearance is suggested to play a prominent role in exacerbating autoimmunity and disease severity. Serologic evidence of exposure to SARS-CoV-2 has a minor impact on the SLE course in a Swedish cohort reportedly. Herein, we assessed NET formation in patients from this cohort by neutrophil elastase (NE) activity and the presence of cell-free DNA, MPO-DNA, and NE-DNA complexes and correlated the findings to the clinical parameters. The presence of NE-DNA complexes and NE activity differed significantly in pre-pandemic versus pandemic serum samples. The latter correlated significantly with the hemoglobin concentration, blood cell counts, and complement protein 3 and 4 levels in the pre-pandemic but only with the leukocyte count and neutrophil levels in the pandemic serum samples. Taken together, our data suggest a change, especially in the NE activity independent of exposure to SARS-CoV-2.
ObjectiveTo estimate the prevalence and incidence of SLE in Sweden using a recent patient cohort, and to estimate the proportion and survival of patients with moderate-to-severe disease defined from ...register data.MethodsThis observational cohort study utilized data from national registries. Adult patients were included if they had at least two secondary care visits with a primary diagnosis of SLE from 1 July 2005 to 31 December 2020.Incident patients were defined as those with no prior visits for SLE in at least the previous 4 years. Disease severity was defined using an algorithm based on previous studies.1 2 Overall survival was defined for incident patients from date of first SLE visit (presumed diagnosis date) until death, stratified by severity in the year after diagnosis.ResultsIn total, 10,186 patients were identified, of which 5,076 were diagnosed after 2006. Prevalence increased from 2006 to 2019. The estimated point prevalence of adult SLE was 93.8 per 100,000 on 31 December 2019, and the estimated average incidence rate between 2015 and 2019 was 4.1 per 100,000 (figure 1). Of incident patients (mean age 49.9, 85% females), 61% had a clinical presentation of moderate-to-severe SLE at some point during the year following diagnosis, however patients can transition between severity states over time. The proportion of patients with moderate-to-severe disease stabilised at around 45% by 4 years after diagnosis until the end of follow-up. Compared to mild SLE patients, moderate-to-severe patients had poorer survival. After 10 years, patients with severe SLE in the year following diagnosis had an 80% survival probability compared to 86% for those with mild SLE (HR 1.49, P<0.001). Patients with moderate SLE had an 81% survival probability (HR vs. mild 1.42, P<0.001) (figure 2).ConclusionsThe estimated incidence and prevalence of SLE in Sweden is consistent with previous studies. This is the first study to evaluate moderate-to-severe SLE in Sweden from registers. Previous research has shown that survival in SLE is poorer than for controls, and we show that survival is poorer in patients presenting with moderate-to-severe disease than in mild disease, highlighting the importance of improving care for this patient group.AcknowledgementsThis study was sponsored by AstraZeneca.References Garris C, Jhingran P, Bass D, et al. Healthcare utilization and cost of systemic lupus erythematosus in a US managed care health plan. J Med Econ 2013;16:667–77. Samnaliev M, Barut V, Weir S, et al. Health care utilization and costs in adults with systemic lupus erythematosus in the United Kingdom: A real-world observational retrospective cohort study. EULAR European E-Congress of Rheumatology. Online2020.Abstract O6 Figure 1Incidence and prevalence of SLE (per 100 000)Abstract O6 Figure 2Kaplan-Meier for mortality by disease severity
Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore ...the antibody response including response to omicron virus subvariants (sBA.1 and sBS.2) after third and fourth COVID-19 vaccine doses in Swedish IRD patients treated with immunomodulating drugs compared to controls. Antibody levels to spike wild-type antigens (full-length protein and S1) and the omicron variants sBA.1 and sBA.2 (full-length proteins) were measured. A positive response was defined as having antibody levels over cut-off or ≥fourfold increase in post-vaccination levels for both antigens. Patients with arthritis, vasculitis, and other autoimmune diseases (
= 414), and controls (
= 61) receiving biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) with or without conventional synthetic DMARDs participated. Of these, blood samples were available for 370 patients and 52 controls after three doses, and 65 patients and 15 controls after four doses. Treatment groups after three vaccine doses were rituximab (
= 133), abatacept (
= 22), IL6r inhibitors (
= 71), JAnus Kinase inhibitors (JAK-inhibitors) (
= 56), tumor necrosis factor inhibitor (TNF-inhibitors) (
= 61), IL12/23/17 inhibitors (
= 27), and controls (
= 52). The percentage of responders after three and four vaccine doses was lower in rituximab-treated patients (59% and 57%) compared to controls (100%) (
< 0.001). After three doses, the percentage of responders in all other groups was 100%, including response to omicron sBA.1 and sBA.2. In rituximab-treated patients, higher baseline immunoglobulin G (IgG) and longer time-period between rituximab and vaccination predicted better response. In this Swedish nationwide study including IRD patients three and four COVID-19 vaccine doses were immunogenic in patients treated with IL6r inhibitors, TNF-inhibitors, JAK-inhibitors, and IL12/23/17-inhibitors but not in rituximab. As >50% of rituximab patients responded to vaccines including omicron subvariants, these patients should be prioritized for additional vaccine doses.
Results from this study provide further evidence that additional doses of COVID-19 vaccines are immunogenic and result in satisfactory antibody response in a majority of patients with inflammatory rheumatic diseases (IRD) receiving potent immunomodulating treatments such as biological or targeted disease-modifying anti-rheumatic drugs (DMARDs) given as monotherapy or combined with traditional DMARDs. We observed that rituximab treatment, both as monotherapy and combined with csDMARDs, impaired antibody response, and only roughly 50% of patients developed a satisfactory antibody response including response to omicron subvariants after the third vaccine. In addition, higher IgG levels at the last rituximab course before the third vaccine dose and a longer time after the last rituximab treatment increased the chance of a satisfactory antibody response. These results indicate that rituximab-treated patients should be prioritized for additional vaccine doses.
EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with number 2021-000880-63.
Objective Antinuclear antibody (ANA) analysis by immunofluorescence (IF) microscopy remains a diagnostic hallmark of systemic lupus erythematosus (SLE). The clinical relevance of ANA ...fine-specificities in SLE has been addressed repeatedly, whereas studies on IF-ANA staining patterns in relation to disease manifestations are very scarce. This study was performed to elucidate whether different staining patterns associate with distinct SLE phenotypes. Design Observational cohort study. Setting One university hospital rheumatology unit in Sweden. Participants The study population consisted of 222 cases (89% women; 93% Caucasians), where of 178 met ≥4/11 of the 1982 American College of Rheumatology (ACR-82) criteria. The remaining 20% had an SLE diagnosis based on positive IF-ANA (HEp-2 cells) and ≥2 typical organ manifestations at the time of diagnosis (Fries’ criteria). Outcome measures The IF-ANA staining patterns homogenous (H-ANA), speckled (S-ANA), combined homogenous and speckled (HS-ANA), centromeric (C-ANA), nucleolar (N-ANA)±other patterns and other nuclear patterns (oANA) were related to disease manifestations and laboratory measures. Antigen-specificities were also considered regarding double-stranded DNA (Crithidia luciliae) and the following extractable nuclear antigens: Ro/SSA, La/SSB, Smith antigen (Sm), small nuclear RNP (snRNP), Scl-70 and Jo-1 (immunodiffusion and/or line-blot technique). Results 54% of the patients with SLE displayed H-ANA, 22% S-ANA, 11% HS-ANA, 9% N-ANA, 1% C-ANA, 2% oANA and 1% were never IF-ANA positive. Staining patterns among patients meeting Fries’ criteria alone did not differ from those fulfilling ACR-82. H-ANA was significantly associated with the 10th criterion according to ACR-82 (‘immunological disorder’). S-ANA was inversely associated with arthritis, ‘immunological disorder’ and signs of organ damage. Conclusions H-ANA is the dominant IF-ANA pattern among Swedish patients with SLE, and was found to associate with ‘immunological disorder’ according to ACR-82. The second most common pattern, S-ANA, associated negatively with arthritis and organ damage.
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