Th17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets.

Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. DD patients often have skin involvement characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. The aim of this study was to characterize the cutaneous immune infiltrate in DD skin lesions in detail and to identify new therapeutic targets. Using gene and protein expression profiling assays including scRNA sequencing, we demonstrate enhanced expression of Th17-related genes and cytokines and increased numbers of Th17 cells in six DD patients. We provide evidence that targeting the IL-17/IL-23 axis in a case series of three DD patients with monoclonal antibodies is efficacious with significant clinical improvement. As DD is a chronic, relapsing disease, our findings might pave the way toward additional options for the long-term management of skin inflammation in patients with DD.

Altered cellular immune response to vaccination against SARS-CoV-2 in patients suffering from autoimmunity with B-cell depleting therapy.

B-cell depleting therapies result in diminished humoral immunity following vaccination against COVID-19, but our understanding on the impact on cellular immune responses is limited. Here, we performed a detailed analysis of cellular immunity following mRNA vaccination in patients receiving B-cell depleting therapy using ELISpot assay and flow cytometry. Anti-SARS-CoV-2 spike receptor-binding domain antibody assays were performed to elucidate B-cell responses. To complement our cellular analysis, we performed immunophenotyping for T- and B-cell subsets. We show that SARS-CoV-2 vaccination using mRNA vaccines elicits cellular T-cell responses in patients under B-cell depleting therapy. Some facets of this immune response including TNFα production of CD4+ T-cells and granzyme B production of CD8+ T-cells, however, are distinctly diminished in these patients. Consequently, it appears that the finely coordinated process of T-cell activation with a uniform involvement of CD4+ and CD8+ T-cells as seen in HCs is disturbed in autoimmune patients. In addition, we observed that immune cell composition does impact cellular immunity as well as sustainability of anti-spike antibody titers. Our data suggest disturbed cellular immunity following mRNA vaccination in patients treated with B-cell depleting therapy. Immune cell composition may be an important determinant for vaccination efficacy.

The role of tender and swollen joints for the assessment of inflammation in PsA using ultrasound.

OBJECTIVE: To evaluate tender joints (TJ) and swollen joints (SJ) for the assessment of ultrasound (US) defined inflammation in PsA. METHODS: Eighty-three PsA patients underwent clinical and US examinations at two scheduled study visits 12 months apart. Tenderness and swelling were assessed at 68 and 66 joints, respectively, and US examinations were conducted at all 68 joints. At patient level, associations with clinical composites and US scores were performed using correlations and by analysing patients with predominantly tender (pTender) or swollen joints (pSwollen). At joint level, a Power Doppler (PD) value ≥ 1 was defined as active synovitis. A generalized linear mixed model was created to assess the predictive value of TJ and SJ for active synovitis after 12 months. RESULTS: SJC showed better correlations with GS/PD scores (r = 0.37/0.47) than with TJC (PD: r = 0.33), while TJC correlated better with patient reported outcomes (PROMs) like patient global assessment (TJC: r = 0.57; SJC r = 0.39). Patients with pTender showed poorer results for PROMs and disease activity scores than patients with pSwollen, but not for laboratory or US markers of inflammation. Swollen joints showed active synovitis in 35% of cases, while only 16% of tender joints were active according to US. Swelling at baseline better predicted active synovitis at the same joint after 12 months [odds ratio (OR) 6.33, P <0.001] as compared with tenderness (OR 3.58, P <0.001). CONCLUSIONS: SJ are more closely linked with US signs of inflammation as compared with TJ in PsA. Joint swelling is a better predictor for signs of US inflammation than tenderness after one year of follow-up.

The Experiences of Functioning and Health of Patients With Primary Sjögren's Syndrome: A Multicenter Qualitative European Study.

Objective: To identify a spectrum of perspectives on functioning and health of patients with primary Sjögren's syndrome (pSS) from the five European countries in order to reveal commonalities and insights in their experiences. Methods: A multicenter focus group study on the patients with pSS about their perspectives of functioning and health was performed. Focus groups were chaired by trained moderators based on an interview guide, audiotaped, and transcribed. After conducting a meaning condensation analysis of each focus group, we subsequently combined the extracted concepts from each country and mapped them to the International Classification of Functioning, Disability and Health (ICF). Results: Fifty-one patients with pSS participated in 12 focus groups. We identified a total of 82 concepts meaningful to people with pSS. Of these, 55 (67%) were mentioned by the patients with pSS in at least four of five countries and 36 (44%) emerged in all the five countries. Most concepts were assigned to the ICF components activities and participation (n = 25, 30%), followed by 22 concepts (27%) that were considered to be not definable or not covered by the ICF; 15 concepts (18%) linked to body structures and functions. Participants reported several limitations in the daily life due to a mismatch between the capabilities of the person, the demands of the environment and the requirements of the activities. Conclusion: Concepts that emerged in all the five non-English speaking countries may be used to guide the development and adaption of the patient-reported outcome measures and to enhance the provision of treatment options based on the aspects meaningful to patients with pSS in clinical routine.

A Pilot Study: Hypertension, Endothelial Dysfunction and Retinal Microvasculature in Rheumatic Autoimmune Diseases.

BACKGROUND: The etiology of autoimmune rheumatic diseases is unknown. Endothelial dysfunction and premature atherosclerosis are commonly seen in these patients. Atherosclerosis is considered one of the main causes of cardiovascular diseases. Hypertension is considered the most important traditional cardiovascular risk. This case-control study aimed to investigate the relationship between autoimmune diseases and cardiovascular risk. METHODS: This study was carried out in patients with rheumatoid arthritis, RA (n = 10), primary Sjögren syndrome, PSS (n = 10), and healthy controls (n = 10). Mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse wave velocity (PWV, an indicator of arterial stiffness) were assessed via a Vicorder device. Asymmetric dimethylarginine (ADMA) was measured via ELISA. Retinal photos were taken via a CR-2 retinal camera, and retinal microvasculature analysis was carried out. T-tests were conducted to compare the disease and control groups. ANOVA and ANOVA-ANCOVA were also used for the correction of covariates. RESULTS: A high prevalence of hypertension was seen in RA (80% of cases) and PSS (40% of cases) compared to controls (only 20% of cases). Significant changes were seen in MBP (RA 101 ± 11 mmHg; PSS 93 ± 10 mm Hg vs. controls 88 ± 7 mmHg, p = 0.010), SBP (148 ± 16 mmHg in RA vs. 135 ± 16 mmHg in PSS vs. 128 ± 11 mmHg in control group; p = 0.007), DBP (77 ± 8 mmHg in RA, 72 ± 8 mmHg in PSS vs. 67 ± 6 mmHg in control; p = 0.010 in RA compared to the controls). Patients with PSS showed no significant difference as compared to controls (MBP: p = 0.240, SBP: p = 0.340, DBP: p = 0.190). Increased plasma ADMA was seen in RA (0.45 ± 0.069 ng/mL) and PSS (0.43 ± 0.060 ng/mL) patients as compared to controls (0.38 ± 0.059 ng/mL). ADMA in RA vs. control was statistically significant (p = 0.022). However, no differences were seen in ADMA in PSS vs. controls. PWV and retinal microvasculature did not differ across the three groups. CONCLUSIONS: The prevalence of hypertension in our cohort was very high. Similarly, signs of endothelial dysfunction were seen in autoimmune rheumatic diseases. As hypertension and endothelial dysfunction are important contributing risk factors for cardiovascular diseases, the association of hypertension and endothelial dysfunction should be monitored closely in autoimmune diseases.

Go Ask Your Patients! PSS-QoL Reported Perception of Dryness Correlates With Lacrimal and Salivary Flow in Primary Sjögren's Syndrome.

Introduction/Objectives: The patient perspective is an essential outcome parameter in the quest for effective therapy in primary Sjögren's Syndrome (PSS). The EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is recommended by EULAR to quantify patient's symptom burden and has been used in several clinical trials. Surprisingly, the patient's perception of dryness quantified with ESSPRI does not correlate with objective measures of salivary or lacrimal flow. Thus, we evaluated a newly developed assessment tool-the Primary Sjögren's Syndrome Quality of Life Questionnaire (PSS-QoL)-for quantifying symptoms of dryness in comparison with the ESSPRI and objective measurements of salivary and lacrimal flow. Methods: Data of patients from the PSS registry of the Medical University of Graz fulfilling the 2016 ACR/EULAR classification criteria for PSS were analyzed. The patient perspective was analyzed by PSS-QoL, ESSPRI, Xerostomia Inventory (XI) and Ocular Surface Disease Index (OSDI). Sicca signs were measured with Schirmer's test, unstimulated salivary flow test (USF) and stimulated salivary flow test (SSF). ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index) and EGA (Evaluator Global Assessment, numeric rating scale from 0 to 10) were obtained. In addition, free light chains (FLC) κ and λ, rheumatoid factor (RF) IgM and IgA were determined. Results: Data from 123 PSS patients were analyzed; 91.9% (n = 113) were female, with a mean disease duration of 6.2 (±5.3) years and mean age of 60.1 (±12.4) years. PSS-QoL-dryness revealed significant negative correlations with Schirmer's test (r = -0.31, p < 0.05) and SSF-test (r = -0.390, p < 0.01). In contrast, we found no significant correlation between ESSPRI-dryness and any objective dryness test. Lower perceived dryness was associated with higher immunological activity determined by increased levels of IgG, FLC and RF-IgA. Whereas patients with only subjective signs of dryness had lower immunological activity. Discussion: Patients' perception of dryness assessed by PSS-QoL correlates with objective measurements of salivary gland function while ESSPRI-dryness did not. Based on the PSS-QoL and objective measures of dryness two distinct groups of PSS patients could be distinguished, which may have implications in daily practice and future clinical studies.

High Prevalence of Ultrasound Verified Enthesitis in Patients With Inflammatory Bowel Disease With or Without Spondylarthritis.

Background: Inflammatory bowel disease (IBD) is closely associated with spondylarthritis (SpA) and enthesitis, as an important feature of SpA, is a common extraintestinal manifestation of IBD. Enthesitis may be clinically silent in a high proportion of patients with IBD without clinical signs or a diagnosis of SpA. Objectives: The aim of this study was to compare the prevalence of ultrasound (US) verified enthesitis in IBD patients with and without SpA, with patients with irritable bowel syndrome (IBS) and healthy subjects (HC) serving as controls. Methods: IBD patients with or without SpA, patients with IBS and HC were prospectively recruited and clinically assessed. Ultrasound examination was performed at 14 entheses. The ultrasound abnormalities were scored according to the Madrid Ankylosing Spondylitis Enthesitis Index (MASEI). Results: We included 33 IBD patients without SpA, 14 IBD patients with SpA, 26 IBS patients and 18 HC. Higher MASEI scores were found in patients with IBD without SpA [median 21.0 range (8.0-53.0)] and IBD associated SpA [33.0 (8-50)] than in IBS patients [10.5 (0-42.0)-p < 0.001 for both comparison] and HC [12.0 (2.0-38.0)-p < 0.01]. PD, enthesophytes and erosions were more common in patients with IBD with or without SpA as compared to IBS patients and HC. IBD patients with SpA compared to IBD without SpA demonstrated significant higher prevalence of erosion and structural irregularity and consequently significant higher MASEI (p < 0.05 for all comparison). Conclusions: Ultrasound verified enthesitis is more common in patients with IBD with or without SpA as compared to patients with IBS or HC.

Lymphopenia in primary Sjögren's syndrome is associated with premature aging of naïve CD4+ T cells.

OBJECTIVE: To investigate peripheral lymphopenia, a frequent finding in primary Sjögren's syndrome (pSS) associated with higher disease activity and increased mortality. METHODS: Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells were purified by MACS technology. In vitro proliferation and senescence-associated ß-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP). RESULTS: In pSS, lymphopenia mainly affected naïve CD4+ T cells. We noted a lower frequency of proliferating naïve CD4+ T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naïve CD4+ T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naïve CD4+ T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers. CONCLUSION: In pSS, evidence for increased proliferation of naïve CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naïve CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.

The use and diagnostic value of testing myositis-specific and myositis-associated autoantibodies by line immuno-assay: a retrospective study.

AIMS: Line immune-assays (LIA) for the detection of myositis-specific antibodies (MSA) are used widely for characterization of idiopathic inflammatory myopathies (IIM). Their current use and significance for the diagnosis of IIM remains unclear. METHODS: In this retrospective analysis, we retrieved clinical diagnoses of patients tested for MSA and myositis-associated antibodies (MAA) Jo-1, Mi-2α, Mi-2ß, TIF1γ, SRP, MDA-5, NXP-2, SAE, PL-7, PL-12, EJ, OJ, PM-Scl100, PM-Scl75 and Ku. We calculated clinical specificity, clinical sensitivity, negative- and positive predictive values (PPV) as well as positive and negative likelihood ratios. RESULTS: In total, we analyzed 3167 samples. After exclusion of repeated measurements and patients with insufficient clinical information, data of 1118 patients were available for analysis. A total of 242 patients tested positive for at least one antibody, of which 45 patients had a diagnosis of IIM; 25 IIM patients were negative for all MSA/MAA. Clinical specificity of MSA/MAA for the diagnosis of IIM ranged between 94.2% and 99.9%. Clinical sensitivity and PPV across all antibodies tested ranged from 0.0% to 12.9% and 0.0% to 72.7%, respectively. CONCLUSION: In clinical practice MSA/MAA are used widely for diagnostic work-up of IIM, resulting in a low pre-test probability. Clinicians should be aware that PPVs for most MSA/MAA are low.

Effects of Probiotic Strains on Disease Activity and Enteric Permeability in Psoriatic Arthritis-A Pilot Open-Label Study.

(1) Background: Psoriatic Arthritis (PsA) is a painful disease of the joints and spine. Recent reports observed distinct enteric dysbiosis in PsA; intake of probiotic strains is considered to ameliorate enteric dysbiosis. If probiotics are effective in PsA is elusive. (2) Methods: In this pilot open-label study we enrolled 10 PsA patients with low to medium disease activity who received probiotics for 12 weeks. Analysis of faecal zonulin, α1-antitrypsin and calprotectin, as well as peripheral immune phenotyping was performed at baseline, after 12 weeks and 12 weeks after termination of probiotic intake. (3) Results: All patients showed increased levels of the enteric permeability marker zonulin which correlated with the frequency of peripheral Th17 cells. Calprotectin, a marker for intestinal inflammation was elevated in 6 out of 10 patients. Probiotic intake resulted in a reduction of disease activity and gut permeability. These effects, however, were not sustained beyond termination of probiotic intake. (4) Conclusions: PsA patients suffer from enhanced enteric permeability and inflammation. Probiotics may ameliorate disease activity in PsA by targeting these alterations.

Ultrasound verified enthesophytes are associated with radiographic progression at entheses in psoriatic arthritis.

OBJECTIVES: The aim of this prospective study was to examine whether ultrasound or clinical abnormalities at enthesal sites predict radiographic progression at entheses in psoriatic arthritis (PsA). METHODS: Consecutive PsA patients were included and subjected to clinical and ultrasound assessments at 14 entheses at baseline, 6 and 12 months. Radiographs were performed at 0 and 12 months. By US, we investigated structural (erosions, osteophytes) and inflammatory changes [grey scale (0-32) and power Doppler (0-14, range global ultrasound score 0-140)], and radiographs were evaluated for enthesophytes and erosions (score range 0-56). Multivariate regression models were conducted to identify the possible association of clinical and ultrasound findings with radiographic progression. RESULTS: We examined 83 patients at baseline, of whom 43 (51.8%) had complete clinical, ultrasound and X-ray data. Twenty-four of 43 patients (55.8%) developed radiographic progression of entheses. These patients were younger (49.6 vs 59.3, P =0.005), had shorter disease duration (9.7 vs 17.9 years, P=0.015) and lower clinical disease activity at 6-months [disease activity in psoriatic arthritis (DAPSA) 6.7 vs 17.0, P=0.018] as compared with patients without progression. Non-progressors had higher ultrasound enthesophyte scores at baseline than progressors (20 vs 15, P<0.05). The multivariate regression analysis revealed that 48.6% of the variance of the X-ray score at 12-months follow-up (RegcoeffB = 0.827, P=0.000) could be explained by the baseline US enthesophyte score. CONCLUSION: Our data indicate that radiographic progression at entheses is linked with age, disease duration and ultrasound verified enthesophytes at baseline. No other ultrasound parameter predicted radiographic progression at entheses.

Helpful, albeit hazardous! Esophageal stem-cell injection in systemic sclerosis.

BACKGROUND: Over 90% of patients with systemic sclerosis suffer from gastroesophageal reflux. Esophageal motility disturbances are associated with a reduced life quality and may force interstitial lung disease progression. We wanted to determine whether we can improve gastroesophageal reflux in these patients by esophageal stem-cell injection. METHODS: We performed a pilot study including eights patients with systemic sclerosis and symptomatic gastroesophageal reflux. Sampling of adipose tissue was performed by an experienced plastic surgeon under local anesthesia. The collected fat was injected into the submucosa of the distal esophagus, each time 1 ml in all four quadrants starting 2, 4 and 6 cm proximal to the Z line (ending up to a total volume of 12 ml). Before the intervention, 3, 6 and finally 12 months after the procedure, patients answered the Gastroesophageal Reflux Disease Health-Related Quality of Life Questionnaire (GERD HRQL) and a high-resolution manometry was performed to quantify changes in motility function. RESULTS: All patients showed an improvement in the GERD HRQL score after the stem-cell injection and a lower dosage of proton-pump inhibitors. The manometric findings showed no change throughout the time. A serious adverse event occurred, as one patient developed multiple cerebellar embolic infarcts. CONCLUSION: Because of the favorable effect in all patients, a safe route for esophageal fat injection needs to be developed.

Evaluating current definitions of low disease activity in psoriatic arthritis using ultrasound.

OBJECTIVE: To evaluate low disease activity (LDA) cut-offs in psoriatic arthritis (PsA) using ultrasound. METHODS: Eighty-three PsA patients underwent clinical and ultrasound examinations at two visits. LDA was assessed using the Disease Activity index for Psoriatic Arthritis (DAPSA ⩽ 14), the Psoriatic ArthritiS Disease Activity Score (PASDAS ⩽ 3.2), the Composite Psoriatic Disease Activity Index ⩽ 4, the DAS28-CRP ⩽ 2.8 and the minimal disease activity criteria. Ultrasound was performed at 68 joints and 14 entheses. Minimal ultrasound disease activity (MUDA-j/e) was defined as a Power Doppler score ⩽ 1, respectively at joints, paratendinous tissue, tendons and entheses. A global ultrasound score was calculated by summing Grey Scale and Power Doppler information (GUIS-j/e). RESULTS: LDA was present in 33.7-65.0% at baseline and in 44.3-80.6% at follow-up, depending on the criteria used. MUDA-j/e was observed in 16.9% at baseline and in 30% at follow-up. GUIS-j/e was significantly higher in patients with moderate/high disease activity vs LDA according to DAPSA and PASDAS at baseline and DAPSA, PASDAS, Composite Psoriatic Disease Activity Index and minimal disease activity at follow-up. Patients in moderate/high disease activity had MUDA-j/e in 8.1-21.4% at baseline and in 8.3-20.0% at follow-up, depending on the applied clinical composite. MUDA-j/e patients with moderate/high disease activity had higher levels of pain and pain-related items than those with LDA. CONCLUSION: The LDA cut-offs of DAPSA, PASDAS, Composite Psoriatic Disease Activity Index, minimal disease activity, but not DAS28-CRP are capable of distinguishing between high and low ultrasound activity. Pain and pain-related items are the main reason why PsA patients without signs of ultrasound inflammation are classified with higher disease activity.

I do not want to suppress the natural process of inflammation: new insights on factors associated with non-adherence in rheumatoid arthritis.

BACKGROUND: It is estimated that 50-70% of patients with rheumatoid arthritis (RA) are non-adherent to their recommended treatment. Non-adherent patients have a higher risk of not reaching an optimal clinical outcome. We explored factors associated with nonadherence from the patient's perspective. METHODS: Four hundred and fifty-nine RA patients (346 (75.4%) females; mean age 63.0 ± 14.8 years) who failed to attend follow-up visits in two rheumatology centres were eligible to participate in a qualitative interview study. We used this strategy to identify patients who were potentially non-adherent to medicines and/or non-pharmacological interventions. By means of meaning condensation analysis, we identified new and some already well known insights to factors associated with non-adherence. We used the capability, opportunity, and motivation model of behaviour (COM-B) model as a frame of reference to classify the factors. RESULTS: Forty-three of 131 patients (32.8%) who agreed to participate in the qualitative interviews were found to be non-adherent. New insights on factors associated with non-adherence included strong opinions of patients, such as pain being considered as an indicator of hard work and something to be proud of, or inflammation being a natural process that should not be suppressed; feeling not to be in expert's hands when being treated by a physician/health professional; the experience of excessive self-control over the treatment; and rheumatologists addressing only drugs and omitting non-pharmacological aspects. The COM-B model comprehensively covered the range of our findings. CONCLUSIONS: The new insights on factors associated with non-adherence allow a better understanding of this phenomenon and can substantially enhance patient care by helping to develop targeted interventions.

Assessing health-related quality of life in primary Sjögren's syndrome-The PSS-QoL.

OBJECTIVES: To develop a questionnaire for the assessment of health-related quality of life (HRQL) in primary Sjögren's syndrome (PSS), and to test its psychometric properties. METHODS: Based on the concepts of a previous qualitative study, a questionnaire for the assessment of HRQL in PSS (PSS-QoL) was developed. Psychometric testing of PSS-QoL was performed after revising the first draft with feedback of patients (n = 6) and clinicians (n = 4). Convergent construct validity was assessed by correlating the score with the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and Euro-QoL 5D (EQ-5D). Reliability was examined by asking patients to complete the questionnaire twice 1-2 weeks apart. An English Version of the PSS-QoL was developed by using standard methodology with forward and back translation. RESULTS: Out of the 75 PSS patients, 91% were female, mean (±SD) age was 58.5 ± 12.5 years. PSS-QoL consists of 25 questions and can be divided into two main categories: physical (discomfort and dryness) and psychosocial. The internal consistency of the PSS-QoL revealed a Crohnbach's α of 0.892. Strong and moderate correlations were found between the PSS-QoL and ESSPRI (corrcoeff = 0.755) and EQ. 5D-pain/discomfort (corrcoeff = 0.531). Reproducibility of the PSS-QoL was high, yielding an ICC of 0.958 (95% CI: 0.926-0.981). CONCLUSIONS: The PSS-QoL is the first specific tool for the assessment of patients' HRQL in PSS and showed good psychometric properties. It may serve as a novel patient-reported outcome measure in future clinical studies.