Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.

[Macrocytic anemia and polychondritis: VEXAS syndrome]. / Makrozytäre Anämie und Polychondritis: VEXAS-Syndrom.

An adult-onset autoinflammatory syndrome caused by somatic mutations in the UBA1 gene on the X chromosome was first reported in 2020. This VEXAS syndrome (acronym for vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) is characterized by an overlap of rheumatic inflammatory diseases with separate hematologic abnormalities. A substantial number of affected patients suffer from treatment refractory relapsing polychondritis and nearly always show signs of macrocytic anemia. This case report illustrates the diagnostic key points to recognizing patients with VEXAS syndrome.

Sleep behaviour differs in women and men with psoriatic arthritis and axial spondyloarthritis with impact on quality of life and depressive symptoms.

OBJECTIVES: Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) may have a profound impact on sleep and health-related quality of life. The aim of this study was to assess sleep quality and quality of life and determine associated factors in patients treated with spondyloarthritides (SpA). METHODS: Cross-sectional questionnaire-based assessment of sleep behaviour, quality of life, functional impairment and depression (Regensburg Insomnia Scale, WHO Quality of Life questionnaire, Funktionsfragebogen Hannover questionnaire, Beck Depression Inventory II, Patient health questionnaire 9) and retrospective medical chart analysis of a monocentric cohort of 330 patients with SpA (n=168 PsA and n=162 axSpA). RESULTS: 46.6% of patients with SpA demonstrated abnormal sleep behaviour. Linear regression models showed HLA-B27 positivity, Bath Ankylosing Spondylitis Disease Activity Index, depressive symptoms, functional capacity and disease duration to be predictive of insomnia symptoms in axSpA, respectively, depressive symptoms, female sex and Disease Activity Score 28 in patients with PsA. Patients with unrestful sleep had a significantly reduced health-related quality of life (p<0.001) as well as significantly more depressive symptoms (p<0.001). Satisfaction with health was rated significantly lower (p<0.001), indicating poor sleep as a burden on general well-being.In particular, female patients had a significantly worse sleep quality with a prolonged sleep latency (p=0.009), increased sleep disturbances (p=0.014) and unrestful sleep (p<0.001) as well as a reduced physical and mental health-related quality of life (p=0.015, p<0.001) and more depressive symptoms (p=0.015). CONCLUSION: Despite treatment, many patients with SpA demonstrate abnormal sleep behaviour with symptoms of insomnia and a reduced quality of life with significant differences between male and female patients. An interdisciplinary and holistic approach may be needed to address unmet needs.

Case Report: Effective and Safe Treatment With Certolizumab Pegol in Pregnant Patients With Cogan's Syndrome: A Report of Three Pregnancies in Two Patients.

Cogan's syndrome is a rare autoimmune disease characterized by ocular inflammation and audiovestibular manifestations. Treatment consists of systemic glucocorticoids and other immunosuppressive agents including methotrexate, cyclophosphamide and TNF-α-inhibitors. Due to potential ovarian or fetal toxicity immunosuppressive treatment options are limited during pregnancies. Thus far there is a paucity of reports on pregnancies in Cogan's syndrome. With minimal transplacental transfer, Certolizumab pegol is considered to be safe for the use in pregnant patients with underlying inflammatory diseases. However, there is no literature on the use of this TNF-α-inhibitor in Cogan's syndrome in general and especially during gestation. Here we report three pregnancies in two Cogan's Syndrome-patients treated with Certolizumab pegol. Treatment with Certolizumab pegol was effective and well tolerated in patients with Cogan's syndrome and seems to be a safe treatment option during pregnancy.

Video clip assessment of a salivary gland ultrasound scoring system in Sjögren's syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise.

OBJECTIVE: To develop ultrasound (US) definitions and a US novel scoring system for major salivary gland (SG) lesions in patients with primary Sjögren's syndrome (pSS) and to test their intrareader and inter-reader reliability using US video clips. METHODS: Twenty-five rheumatologists were subjected to a three-round, web-based Delphi process in order to agree on (1) definitions and scanning procedure of salivary gland ultrasonography (SGUS): parotid, submandibular and sublingual glands (PG, SMG and SLG); (2) definitions for the elementary SGUS lesions in patients with Sjögren's syndrome; (3) scoring system for grading changes. The experts rated the statements on a 1-5 Likert scale. In the second step, SGUS video clips of patients with pSS and non-pSS sicca cases were collected containing various spectrums of disease severity followed by an intrareader and inter-reader reliability exercise. Each video clip was evaluated according to the agreed definitions. RESULTS: Consensual definitions were developed after three Delphi rounds. Among the three selected SGs, US assessment of PGs and SMGs was agreed on. Agreement was reached to score only greyscale lesions and to focus on anechoic/hypoechoic foci in a semiquantitative matter or, if not possible on a qualitatively (present/absent) evaluation of fatty or fibrous lesions. Intrareader reliability for detecting and scoring these lesions was excellent (Cohen's kappa 0.81) and inter-reader reliability was good (Light's kappa 0.66). CONCLUSION: New definitions for developing a novel semiquantitative US score in patients with pSS were developed and tested on video clips. Inter-reader and intrareader reliabilities were good and excellent, respectively.

Whipple's disease mimicking rheumatoid arthritis can cause misdiagnosis and treatment failure.

BACKGROUND: Whipple's disease, a rare chronic infectious disorder caused by Tropheryma whipplei, may present with predominant joint manifestations mimicking rheumatoid arthritis (RA). METHODS: A retrospective single-center cohort study of seven patients was performed. Clinical symptoms were assessed by review of medical charts and Whipple's disease was diagnosed by periodic-acid-Schiff-stain and/or Tropheryma whipplei-specific polymerase-chain-reaction. RESULTS: Median age at disease onset was 54 years, six patients were male. Median time to diagnosis was 5 years. All patients presented with polyarthritis with a predominantly symmetric pattern. Three had erosive arthritis. Affected joints were: wrists (5/7), metacarpophalangeal joints (MCPs) (5/7), knees (5/7), proximal interphalangeal joints (PIPs) (3/7), hips (2/7), elbow (2/7), shoulder (2/7). All patients had increased C-reactive-protein concentrations, while rheumatoid factor and anti-CCP-antibodies were absent, and were initially (mis)classified as RA-patients according to EULAR/ACR-criteria (median DAS28 4.3). Six patients received antirheumatic treatment consisting of prednisone with methotrexate and/or leflunomide, three were additionally treated with at least one biologic agent (abatacept, adalimumab, etanercept, rituximab, tocilizumab). Most patients showed insufficient treatment response. In all patients Tropheryma whipplei was detected in synovial fluid by polymerase-chain-reaction; in three patients the diagnosis of Whipple's disease was further ascertained by periodic-acid-Schiff-staining. Gastrointestinal symptoms and other extra-articular manifestations were absent, mild or non-specific. Treatment was initiated with trimethoprin/sulfamethoxazole in five and doxycycline/hydroxychloroquine in two patients and had to be adapted in five patients. Finally, all patients had good treatment responses with improvement of arthritis and extra-articular manifestations. CONCLUSION: Whipple's disease is rare and can mimic rheumatoid arthritis. Especially patients with seronegative rheumatoid arthritis with a prolonged disease course and insufficient treatment response should be reevaluated for Whipple's disease.

Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency.

PURPOSE: The aim of this study was to identify characteristics of hypogammaglobulinemia secondary to glucocorticoid therapy and their value in the differential diagnosis to primary forms of antibody deficiency. METHODS: We investigated prevalence and character of hypogammaglobulinemia in a cohort of 36 patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) on glucocorticoid therapy in comparison to a gender- and age-matched cohort of hospital controls. We therefore determined serum immunoglobulin levels as well as B- and T cell-subsets in the peripheral blood of all participants. In addition, prior serum immunoglobulin levels and clinical data of the GCA and PMR patients were extracted from the electronic patient data-base. RESULTS: 21/36 GCA/PMR patients on glucocorticoid treatment developed antibody deficiency. In 19 patients this included IgG and in 13 patients IgG was the only affected isotype. The reduction of IgG was persistent in nearly 50 % of these patients during the observed period. GCA/PMR patients had reduced circulating naive and transitional B cells (p = 0.0043 and p = 0.0002 respectively) while IgM, IgG and IgA memory B cells were preserved. Amongst T-cell subsets, we found a reduction of CD4 memory T cells (p < 0.0001), CD4 regulatory T cells (p = 0.0002) and few CD8 memory T-cell subtypes. CONCLUSION: Persistent humoral immunodeficiency occurs in about a quarter of GCA/PMR patients under glucocorticoid therapy. Because most patients have isolated IgG deficiency, preserved IgA production and class-switched memory B cells, by these markers this form of secondary hypogammaglobulinemia can be clearly distinguished from common variable immunodeficiency (CVID).

MRI displays involvement of the temporalis muscle and the deep temporal artery in patients with giant cell arteritis.

PURPOSE: To assess deep temporal artery and temporalis muscle involvement in patients with giant cell arteritis (GCA). MATERIAL AND METHODS: Ninety-nine patients who received magnetic resonance imaging (MRI) and superficial temporal artery biopsy (TAB) were included in this study. Patients with positive TAB (n = 61) were defined as GCA patients, those with negative TAB (n = 38) as the GCA-negative reference group. Contrast-enhanced T1w-images were acquired utilizing 1.5 T and 3 T MRI. Two radiologists assessed the images. Mural contrast-hyperenhancement and wall thickening of the deep temporal artery and hyperenhancement of the muscle were defined as inflammation. MRI results were correlated with jaw claudication in 70 patients. RESULTS: The two observers found temporalis muscle involvement in 19.7 % (n = 12) and 21.3 % (n = 13) of GCA patients. It occurred bilaterally in 100 %. Specificities were 92/97 % and sensitivities were 20/21 %. Deep temporal artery involvement was found in 34.4 % (n = 21) and 49.2 % (n = 30) and occurred bilaterally in 80/90.5 %. Specificities were 84/95 % and sensitivities were 34/49 %. Both structures were affected simultaneously in 18/21.3 %. Jaw claudication correlated moderately with inflammation of the temporalis muscle (r = 0.31; p < 0.05) and the deep temporal artery (r = 0.38; p = 0.01). CONCLUSION: MRI visualizes changes in the temporalis muscle and the deep temporal artery in GCA. Moderate correlation of clinical symptoms with MRI results was observed. KEY POINTS: • Approximately 20 % of GCA patients presented with temporalis muscle inflammation. • A total of 34-49 % of GCA patients presented with vasculitis of the deep temporal artery. • In approximately 20 % of GCA patients, both structures were simultaneously involved. • Involvement of both structures correlated moderately with presence of jaw claudication. • MRI is a suitable tool for the assessment of vasculitis and muscle inflammation.

Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study.

The dopaminergic system plays a key role in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate (MP), a dopamine (DA) reuptake inhibitor, is a drug of first choice for treating ADHD. This cross-over study investigated alterations in DA metabolism in young males with ADHD who had never been pharmacologically treated and MP-treated patients in comparison to healthy subjects. Dynamic 3,4-dihdroxy-6-[18F]fluorophenyl-L-alanine (FDOPA) PET scans were carried out on 20 male patients with ADHD and 18 healthy men. Eight ADHD patients had never been treated with psychostimulants, the rest had received MP. Based on the tissue-slope-intercept plot parametric images of FDOPA influx rate constant (Ki) were generated for each subject from dynamic 3D FDOPA datasets and transformed into standard stereotactic space. First a volume of interest analysis was performed on each single subject. In a second step data were introduced to a SPM2 analysis to detect significant changes in mean voxel Ki values between the normal control group and each patient group. In comparison to controls, ADHD patients as a group (irrespective of treatment status) showed a lower Ki in bilateral putamen, amygdala and dorsal midbrain. There was a lower Ki in the left putamen, right amygdala and right dorsal midbrain in untreated patients compared to controls together with a relative higher influx in the left amygdala and right anterior cingulate cortex. In contrast, methylphenidate treatment was associated with a significantly lower Ki in the striatum and amygdala bilaterally, and in the right dorsal midbrain. Untreated young adult ADHD patients showed a dopamine dysfunction that might be partly due to compensatory mechanisms. MP seems to down-regulate dopamine turnover. This effect might be one component in the mechanism of action of this drug in ADHD treatment.