Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication.

Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3+/CD4+), lower transitional B cells (CD19+/CD38++/CD10+/IgD+), lower pre-switched memory B cells (CD19+/CD27+/IgD+), and lower post-switched memory B cells (CD19+/CD27+/IgD-). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56+/CD3-). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored.

Clonal expansion of large granular lymphocytes in patients with spondyloarthritis and psoriatic arthritis treated with TNFα inhibitors.

To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.

Anti-CCP status determines the power Doppler oscillation pattern in rheumatoid arthritis: a prospective study.

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction. Serologically, it can be differentiated according to rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP), or both. This differentiation is prognostically and therapeutically relevant. No method has been described to separate the two forms phenotypically. We hypothesize that a differentiation is possible by evaluating oscillation patterns in power Doppler sonography (PDS). In a prospective study, 20 patients with anti-CCP-positive RA and 20 patients with anti-CCP-negative RA with active wrist synovitis were examined. A PDS scan was performed, and perfusion maxima (P max) and minima (P min) as well as the amplitude (ΔP) were determined by a blinded study member. The amplitude was standardized (sΔP) by dividing by P max, and the anti-CCP-positive and anti-CCP-negative patients as well as the RF-positive and RF-negative were compared to each other. In the ultrasonographic evaluation, we found a highly significant difference in sΔP between CCPp and CCPn patients (median 19.0 vs. 42.9 %, p < 0.0001). sΔP is independent of disease activity. The absolute amplitude ΔP did not differ between the groups. Also, in anti-CCP-positive patients there was a completely linear correlation between P max and P min, and this was far less marked in anti-CCP-negative patients. Anti-CCP-positive and anti-CCP-negative RA display different PDS oscillation patterns. This constitutes a nonserological parameter to differentiate between the two forms. The difference in PDS oscillation patterns suggests that the underlying pathological process differs between the forms.

Patient-reported outcomes provide evidence for increased depressive symptoms and increased mental impairment in giant cell arteritis.

Objectives: The spectrum of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) represents highly inflammatory rheumatic diseases. Patients mostly report severe physical impairment. Possible consequences for mental health have been scarcely studied. The aim of this study was to investigate psychological well-being in the context of GCA and PMR. Methods: Cross-sectional study with N = 100 patients with GCA and/or PMR (GCA-PMR). Patient-reported outcomes (PROs) were measured using the Short Form 36 Version 2 (SF-36v2) and visual analog scale (VAS) assessment. Moreover, the Patient Health Questionnaire 9 (PHQ-9) was used in 35 of 100 patients to detect depression. To compare PROs with physician assessment, VAS was also rated from physician perspective. To assess a possible association with inflammation itself, serological parameters of inflammation (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) were included. Results: In all scales of the SF-36v2 except General Health (GH) and in the physical and mental sum score (PCS, MCS), a significant impairment compared to the German reference collective was evident (MCS: d = 0.533, p < 0.001). In the PHQ-9 categorization, 14 of the 35 (40%) showed evidence of major depression disorder. VAS Patient correlated significantly with PHQ-9 and SF-36 in all categories, while VAS Physician showed only correlations to physical categories and not in the mental dimensions. Regarding inflammatory parameters, linear regression showed CRP to be a complementary significant positive predictor of mental health subscale score, independent of pain. Conclusion: PRO show a relevant impairment of mental health up to symptoms of major depression disorder. The degree of depressive symptoms is also distinctly associated with the serological inflammatory marker CRP.

Whole-Body [18F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease.

The 2-deoxy-d-[18F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [18F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [18F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [18F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [18F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [18F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95-1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85-0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95-1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83-1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55-0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57-0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [18F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.

Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis.

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.

Differing X-ray patterns in seronegative and seropositive rheumatoid arthritis.

INTRODUCTION: Anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) status are important predictors for rheumatoid arthritis (RA) erosivity. Qualitative differences on hand/feet radiographs have been described, indicating more carpal fusion in seronegative RA. This study explores these differences further using the total Sharp/van der Heijde score (TSS), digital X-ray radiogrammetry (DXR), and qualitative description. METHODS AND MATERIALS: Matched seronegative (ACPA negative, RF negative, snRA) and seropositive (ACPA, RF > 3xULN, spRA) were examined. TSS scores both for erosions and joint space narrowing (JSN) were registered separately and compared for both groups. Joint compartments and single joints were compared, using a heat map. The degree of carpal fusion was quantified 0-5. DXR measurements (bone mineral density, cortical thickness, bone width, metacarpal index) were determined for each hand separately. Finally, selected radiographs were examined unblinded to search for non-quantifiable differences. RESULTS: A total of 56 snRA and 57 spRA patients were examined. spRA patients had more erosions and joint space narrowing. Erosion load differed significantly between spRA and snRA in the foot and metacarpophalangeal joint, but not in the wrist or proximal interphalangeal joint compartments. Intracompartmental differences were greater in spRA. JSN scores were greater in spRA, in all compartments except wrist. Carpal fusion and DXR scores did not differ between the groups. The qualitative comparison showed that snRA patients displayed periarticular ossifications, carpal shortening, and sparing of the CMC joints, whereas spRA patients had more CMC damage and less shortening. CONCLUSION: X-ray manifestations in snRA and spRA are qualitatively and quantitatively different. This suggests pathophysiological differences between the two forms. Key Points • Seronegative and seropositive RA display qualitatively and quantitatively different X-ray patterns, suggesting differences in the underlying pathophysiological process. This is the first time that this has been shown in a systematic, quantitative fashion.

Correction to: Differing X-ray patterns in seronegative and seropositive rheumatoid arthritis.

The first and family names of the authors were interchanged and are now presented correctly. The original article has been corrected.

Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) is performed in patients with aggressive forms of systemic sclerosis (SSc). The profile of B cell reconstitution after aHSCT is not fully understood. The aim of this study was to investigate changes of B cell subsets and cytokine production of B cells in patients with SSc after aHSCT. METHODS: Peripheral blood of six patients with SSc was collected at defined intervals up to 16 months after aHSCT. Immunophenotyping was performed, and B cell function was determined by measuring cytokine secretion in supernatants of stimulated B cell cultures. RESULTS: Within 1 month after aHSCT, a peak in the percentage of CD38++/CD10+/IgD+ transitional B cells and CD38++/CD27++/IgD- plasmablasts was detected. Long-term changes persisted up to 14 months after aHSCT and showed an increased percentage of total B cells; the absolute B cell number did not change significantly. Within the B cell compartment, an increased CD27/IgD+ naïve B cell percentage was found whereas decreased percentages of CD27+/IgD+ pre-switched memory, CD27+/IgD- post-switched memory, and CD27-/IgD- double-negative B cells were seen after aHSCT. Cytokine secretion in B cell cultures showed significantly increased IL-10 concentrations 13 to 16 months after aHSCT. CONCLUSION: A changed composition of the B cell compartment is present for up to 14 months after aHSCT indicating positive persisting effects of aHSCT on B cell homeostasis. The cytokine secretion profile of B cells changes in the long term and shows an increased production of the immune regulatory cytokine IL-10 after aHSCT. These findings might promote the clinical improvements after aHSCT in SSc patients.

Tocilizumab in Large Vessel Vasculitis - Different Routes of Administration.

BACKGROUND: Tocilizumab is increasingly used in the treatment of large vessel vasculitis with recent approval for giant cell arteritis. OBJECTIVE: To determine the efficacy and safety of tocilizumab in large vessel vasculitis in a real-life setting using different routes of administration. METHODS: Retrospective analysis of consecutive patients at a tertiary rheumatology department who received tocilizumab for large vessel vasculitis. RESULTS: A total of 11 patients were treated with tocilizumab (8 giant cell arteritis, 2 large vessel vasculitis associated with rheumatoid arthritis, 1 Takayasu arteritis) after a median of 2 other steroid-sparing agents (range 1-4). Of these, 9 received tocilizumab as salvage therapy for active vasculitis and 2 due to the toxicity of their former steroid-sparing medication. After a mean follow-up of 23 months 7 patients were in remission as to vasculitis under a mean prednisolone dose of 1.7 ± 1.5 mg; one patient relapsed after long term remission having discontinued tocilizumab for elective surgery; one patient stopped tocilizumab after attributable infectious complications, and two patients died: one due to complications of vascular surgery, probably not attributable to tocilizumab; and the other due to sepsis secondary to sigmoiditis. Only 3 relapses occurred under continuous tocilizumab treatment. In all these 3 cases, renewed remission could be achieved by switching from subcutaneous (162 mg qw) to intravenous tocilizumab (8mg/kg q4w). CONCLUSION: Tocilizumab is efficacious in patients with large vessel vasculitis in a real-life situation. Safety appears to be acceptable, but infectious complications have to be considered. Intravenous tocilizumab may be used in patients who relapse under subcutaneous application.

Management of anti-HBc-positive patients with rheumatic diseases treated with disease-modifying antirheumatic drugs-a single-center analysis of 2054 patients.

Hepatitis B virus (HBV) reactivation is a common complication of immunosuppressive treatment in high prevalence countries. Biological disease-modifying antirheumatic drugs (bDMARDs) cause this adverse event more often than conventional immunosuppressants. The incidence of HBV reactivation during treatment for rheumatic diseases in Germany is unclear. Furthermore, it remains open how to treat and monitor patients at risk during immunosuppressive therapy with bDMARDs. We examined 2054 patients from a German tertiary rheumatology center in order to analyze the prevalence of HBc-antibody-positivity and the incidence of HBV reactivation in German rheumatology patients treated with immunosuppressants. Of 1317 patients treated with bDMARDs and 737 conventional synthetic DMARD (csDMARDs) patients between 2008 and 2017, 86 had a history of HBV infection (anti-HBc positive). Only two patients were suffering from chronic infection (HBsAg positive). Three patients were treated pre-emptively with entecavir, and eight patients after HBV DNA reappearance. No liver failure occurred due to HBV reactivation. Compared to anti-HBc-positive patients without reactivation, the reactivation group included more patients exposed to three or more classes of bDMARDs (p = 0.017). The median HBs antibody titer was significantly lower in the reactivation group (15.0 IU/l vs. 293.5 IU/l; p = 0.001). This study shows that bDMARDs and csDMARDs can safely be administered to patients with a history of HBV, provided they are closely monitored. Low titers of anti-HBs antibodies and a history of ≥ 3 classes of immunosuppressants increase the risk of HBV reactivation. These data highlight major differences to high prevalence regions.

Prevalence and Characteristics of Persistent Clonal T Cell Large Granular Lymphocyte Expansions in Rheumatoid Arthritis: A Comprehensive Analysis of 529 Patients.

OBJECTIVE: Up to one-third of patients with T cell large granular lymphocyte (T-LGL) leukemia display symptoms of rheumatoid arthritis (RA). In Crohn's disease and psoriasis, treatment with tumor necrosis factor (TNF) inhibitors is associated with hepatosplenic γδ T cell lymphoma and with clonal expansion of γδ T cells, respectively. This study was undertaken to determine the prevalence of clonal T-LGL cells in patients with RA and define risk factors for this rare hematologic malignancy. METHODS: A total of 529 RA patients were recruited between November 2013 and August 2015. Eight-color flow cytometry (fluorescence-activated cell sorting [FACS]) was performed to screen for aberrant T cell populations of LGLs. Molecular analysis of the T cell receptor was used to confirm the diagnosis in patients with suggestive FACS findings. Electronic patient files were used to determine risk factors. Patients with clonal populations were monitored prospectively for up to 4 years. RESULTS: The median patient age was 61 years, and 74% were female. The median duration of RA was 12 years. The median Disease Activity Score in 28 joints was 2.8, and 69.9% of patients had ever been treated with biologic disease-modifying antirheumatic drugs. We identified clonal T-LGL expansions in 19 patients, equaling a prevalence of 3.6%. The T-LGL cell clone was constant over time in most patients and was significantly associated with the duration of the exposure to TNF-blocking agents (P = 0.01). No other risk factors could be detected. CONCLUSION: RA patients with long-term exposure to TNF-blocking agents were at a greater risk of developing clonal expansions of LGLs. This finding may prompt clinicians to refrain from using these substances in RA patients with known T cell aberrations.

Vasculitis-like hemorrhagic retinal angiopathy in Wegener's granulomatosis.

BACKGROUND: Granulomatosis with polyangiitis, also known as Wegener's granulomatosis, is a chronic systemic inflammatory disease that can also involve the eyes. We report a case of massive retinal and preretinal hemorrhages with perivascular changes as the initial signs in granulomatosis with polyangiitis (Wegener's granulomatosis). CASE PRESENTATION: A 39-year-old Caucasian male presented with blurred vision in his right eye, myalgia and arthralgia, recurrent nose bleeds and anosmia. Fundus image of his right eye showed massive retinal hemorrhages and vasculitis-like angiopathy, although no fluorescein extravasation was present in fluorescein angiography. Laboratory investigations revealed an inflammation with increased C-reactive protein, elevated erythrocyte sedimentation rate and neutrophil count. Tests for antineutrophil cytoplasmic antibodies (ANCA) were positive for c-ANCA (cytoplasmatic ANCA) and PR3-ANCA (proteinase 3-ANCA). Renal biopsy demonstrated a focal segmental necrotizing glomerulonephritis. Granulomatosis with polyangiitis (Wegener's granulomatosis) was diagnosed and a combined systemic therapy of cyclophosphamide and corticosteroids was initiated. During 3 months of follow-up, complete resorption of retinal hemorrhages was seen and general complaints as well as visual acuity improved during therapy. CONCLUSION: Vasculitis-like retinal changes can occur in Wegener's granulomatosis. Despite massive retinal and preretinal hemorrhages that cause visual impairment, immunosuppressive therapy can improve ocular symptoms.

Lying obliquely--a clinical sign of cognitive impairment: cross sectional observational study.

OBJECTIVE: To determine if failure to spontaneously orient the body along the longitudinal axis of a hospital bed when asked to lie down is associated with cognitive impairment in older patients. DESIGN: Cross sectional observational study. SETTING: Neurology department of a university hospital in Germany. PARTICIPANTS: Convenience sample of 110 older (>or=60 years) inpatients with neurological conditions and 23 staff neurologists. MAIN OUTCOME MEASURES: The main outcome measure was the association between the angle of the body axis and the results of three cognitive screening tests (mini-mental state examination, DemTect, and clock drawing test). Staff doctors were shown photographs of a model taken at a natural viewing able to determine their subjective perspective of what constitutes oblique. RESULTS: 110 neurological inpatients (mean age 70.9 (SD 6.8) years) were included after exclusions. Evidence of cognitive impairment was found in 34, with scores indicating dementia in eight, according to the mini-mental state examination, and in 11 according to the DemTect. Across all patients, the mean angular deviation of the body axis from the longitudinal axis of the bed (range 0-23 degrees ) correlated linearly with the mini-mental state examination (r=-0.480), DemTect (r=-0.527), and the clock drawing test (r=-0.552) scores (P<0.001 for all), even after removing age as a covariate. Overall, 90% of staff neurologists considered a minimal body angle of 7 degrees to be oblique. Angular deviation of at least 7 degrees predicted cognitive impairment according to the three different tests, with specificities between 89% and 96% and sensitivities between 27% and 50%. CONCLUSION: Clinicians might suspect cognitive impairment in mobile older inpatients with neurological disorders who spontaneously position themselves obliquely when asked to lie on a bed.