Distinct Effects of Interleukin-1β Inhibition upon Cytokine Profile in Patients with Adult-Onset Still’s Disease and Active Articular Manifestation Responding to Canakinumab

Adult-onset Still’s disease (AOSD) is a systemic auto-inflammatory disease characterized by the presence of immunologically mediated inflammation and deficient resolution of inflammation. Canakinumab is an approved IL-1β inhibitor in the treatment of AOSD with a balanced efficacy and safety profile. Since inflammatory cytokines play a major role in the pathogenesis of AOSD, we investigated the effects of canakinumab on the cytokine profile of AOSD patients from a randomized controlled trial. Multiplex analysis and ELISA were used to test the concentrations of several cytokines at three time points—week 0 (baseline), week 1 and week 4—in two patient groups—placebo and canakinumab. Two-way repeated-measures analysis of variance revealed a significant temporal effect on the concentrations of MRP 8/14, S100A12, IL-6 and IL-18 with a significant decrease at week 4 in the canakinumab group exclusively. Comparing responders with non-responders to canakinumab showed a significant decrease in MRP 8/14, IL-1RA, IL-18 and IL-6 in responders at week 4, while S100A12 levels decreased significantly in responders and non-responders. In summary, canakinumab showed a striking effect on the cytokine profile in patients with AOSD, exhibiting a clear association with clinical response

Response to abatacept is associated with the inhibition of proteasome β1i expression in T cells of patients with rheumatoid arthritis

Objective: Abatacept is a biological disease-modifying antirheumatic drug (DMARD) used for the treatment of rheumatoid arthritis (RA) and modulates the costimulatory signal by cluster of differentiation (CD)28:CD80/CD86 interaction required for T cell activation. Since CD28-mediated signalling regulates many T cell functions including cytokine production of, for example, interferons (IFNs), it is of interest to clarify, whether response to abatacept has an effect on the IFN inducible immunoproteasome, as a central regulator of the immune response. Methods: Effects of abatacept on the proteasome were investigated in 39 patients with RA over a period of 24 weeks. Using real-time PCR, transcript levels of constitutive and corresponding immunoproteasome catalytic subunits were investigated at baseline (T0), week 16 (T16) and week 24 (T24) in sorted blood cells. Proteasomal activity and induction of apoptosis after proteasome inhibition were also evaluated. Results: Abatacept achieved remission or low disease activity in 55% of patients at T16 and in 70% of patients at T24. By two-way analysis of variance (ANOVA), a significant reduction of proteasome immunosubunit β1i was shown only in CD4+ and CD8+ T cells of sustained responders at both T16 and T24. One-way ANOVA analysis for each response group confirmed the results and showed a significant reduction at T24 in CD4+ and CD8+ T cells of the same group. Abatacept did not influence chymotrypsin-like activity of proteasome and had no effect on induction of apoptosis under exposure to a proteasome inhibitor in vitro. Conclusion: The reduction of proteasome immunosubunit β1i in T cells of patients with RA with sustained response to abatacept suggests association of the immunoproteasome of T cells with RA disease activity

Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease accompanied by muscular fatigue and pain. A functional measure to assess muscle fatigability of ME/CFS patients is, however, not established in clinical routine. The aim of this study is to evaluate by assessing repeat maximum handgrip strength (HGS), muscle fatigability as a diagnostic tool and its correlation with clinical parameters. Methods: We assessed the HGS of 105 patients with ME/CFS, 18 patients with Cancer related fatigue (CRF) and 66 healthy controls (HC) using an electric dynamometer assessing maximal (Fmax) and mean force (Fmean) of ten repetitive measurements. Results were correlated with clinical parameters, creatinine kinase (CK) and lactate dehydrogenase (LDH). Further, maximum isometric quadriceps strength measurement was conducted in eight ME/CFS patients and eight HC. Results: ME/CFS patients have a significantly lower Fmax and Fmean HGS compared to HC (p < 0.0001). Further, Fatigue Ratio assessing decline in strength during repeat maximal HGS measurement (Fmax/Fmean) was higher (p <= 0.0012). The Recovery Ratio after an identical second testing 60 min later was significantly lower in ME/CFS compared to HC (Fmean2/Fmean1; p <= 0.0020). Lower HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and with higher CK and LDH levels after exertion. Conclusion: Repeat HGS assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS

Canakinumab for Treatment of Adult-Onset Still's Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial

Background: Inhibition of interleukin (IL)-1 represents a promising treatment option in adult-onset Still's disease (AOSD). Objective: To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multicentre, double-blind, randomised, placebo-controlled trial. Methods Patients with AOSD and active joint involvement (tender and swollen joint counts of >= 4 each) were treated with canakinumab (4 mg/kg, maximum 300 mg subcutaneous every 4 weeks) or placebo. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12 as determined by the change in disease activity score (Delta DAS28>1.2). Results At enrolment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab and 5.3 in the placebo group, respectively. In the intention-to-treat analysis, 12 patients (67%) in the canakinumab group and 7 patients (41%) in the placebo group fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, p=0.033), ACR 50% (50% vs 6.7%, p=0.009) and ACR 70% (28% vs 0%, p=0.049) response rates were observed in the canakinumab group compared with the placebo group. Two patients in the canakinumab group experienced a serious adverse event. Conclusion Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD

Portal hypertension in common variable immunodeficiency disorders – a single center analysis on clinical and immunological parameter in 196 patients

BackgroundLiver manifestations and in particular portal hypertension (PH) contribute significantly to morbidity and mortality of patients with common variable immunodeficiency disorders (CVID). Screening strategies and early detection are limited due to the lack of specific diagnostic tools.MethodsWe evaluated clinical, immunological, histological, and imaging parameters in CVID patients with clinical manifestation of portal hypertension (CVID+PH).ResultsPortal hypertension was present in 5.6% of CVID patients and was associated with high clinical burden and increased mortality (18%). Longitudinal data on clinical and immunological parameters in patients before and during clinically manifest portal hypertension revealed a growing splenomegaly and increasing gamma-glutamyl transferase (GGT) and soluble interleukin 2 receptor (SIL-2R) levels with decreasing platelets over time. While ultrasound of the liver failed to detect signs of portal hypertension in most affected patients, transient elastography was elevated in all patients. All CVID+PH patients had reduced naïve CD45RA+CD4+ T-cells (mean of 6,2%). The frequency of severe B-lymphocytopenia (Euroclass B-) was higher in CVID+PH patients. The main histological findings included lymphocytic infiltration, nodular regenerative hyperplasia-like changes (NRH-LC), and porto(-septal) fibrosis.ConclusionCVID patients with lower naïve CD45RA+CD4+ T-cells or severely reduced B-cells might be at higher risk for portal hypertension. The combination of biochemical (increasing sIL-2R, GGT, and decreasing platelets) and imaging parameters (increasing splenomegaly) should raise suspicion of the beginning of portal hypertension

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naive healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4(+) T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

A phase II investigator-initiated pilot-study with low-dose cyclosporine A for the treatment of articular involvement in primary Sjögren’s syndrome

Ziel: Diese klinische Studie wurde zur Untersuchung der Wirksamkeit und Sicherheit von niedrig dosiertem Cyclosporin A (CyA) bei Patienten mit primärem Sjögren-Syndrom (pSS) und Gelenkbeteiligung durchgeführt. Methoden: Diese Phase-II-open-label Studie untersuchte 30 Patienten, welche die Kriterien für pSS der amerikanisch-europäischen Konsens Gruppe erfüllten und unter stabiler symptomatischer Therapie eine aktive Gelenkbeteiligung aufwiesen. Niedrigdosiertes CyA (etwa 2 mg/kg Körpergewicht pro Tag) wurde über einen Zeitraum von 16 Wochen oral verabreicht. Der primäre Endpunkt war definiert als eine Reduktion der Anzahl schmerzhafter und/oder geschwollener Gelenke am Ende der Behandlungsphase. Sekundäre Endpunkte waren Untersuchungen zur Veränderung im allgemeinen Gesundheitszustand anhand von Patienten- Fragebögen, der Sicca-Symptome, der Krankheitsaktivität mittels DAS28 (disease activity score an 28 Gelenken) und ESSDAI (EULAR Sjögren’s Syndrome Disease Activity Index – Krankheitsaktivitätsindex für Sjögren Syndrom der Europäischen Liga gegen Rheuma), der Bildgebung mittels Arthrosonographie und des Sicherheitsprofils von CyA. Ergebnisse: Die mittlere Anzahl der druckschmerzhaften Gelenke (68-er Gelenkstatus) war zu Behandlungsbeginn 16,2 (± 13,2) und verbesserte sich signifikant auf 10,4 (± 11,9) (p = 0,002) bei Behandlungsende. Die mittlere Anzahl der geschwollenen Gelenke (66-er Gelenkstatus) wurde von 3,2 (± 3,3) auf 1,3 (± 3,2) durch die Behandlung reduziert (p < 0,001). Der Krankheitsaktivitätsscore (DAS28) zeigte eine klinisch bedeutsame Reduktion über die 16-wöchige Behandlungsperiode (p ≤ 0,001). Die Behandlung wurde gut vertragen und unerwünschte Ereignisse stimmten mit dem bekannten Sicherheitsprofil von CyA überein (z.B. arterielle Hypertonie, Kopfschmerzen). Medizinisch bedeutsame Verbesserungen der allgemeinen Gesundheit und der Sicca-Symptomatik konnten in dieser kurzen Behandlungsphase nicht festgestellt werden. Schlussfolgerung: In dieser Pilotstudie wurden vielversprechende Effekte einer niedrig dosierten CyA- Behandlung auf die Gelenkbeteiligung bei Patienten mit pSS beobachtet, die weitere kontrollierte Studien in dieser Indikation rechtfertigen. Es wurden keine unerwarteten Sicherheitssignale beobachtet. Zur weiteren Untersuchung des Einflusses von CyA auf die allgemeinen Gesundheit, Müdigkeit, Sicca- Symptomatik sind möglicherweise längere Behandlungsphasen erforderlich.Objective: To investigate the efficacy and safety of low-dose cyclosporine A (CyA) in patients with primary Sjögren's syndrome (pSS) and articular involvement. Methods: This Phase II open label clinical study included 30 patients meeting the American-European Consensus group criteria for pSS with active joint involvement under stable symptomatic therapy. Treatment consisted of low dose CyA (approximately 2 mg/kg body weight of CyA per day) over a period of 16 weeks. The primary endpoint was defined as a reduction in the number of painful and/or swollen joints at end of treatment (EOT). Secondary endpoints included the evaluation of changes in general health by assessing patient reported outcomes (PROs), sicca-symptoms, disease activity score with 28 joint count (DAS28), European League against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI), arthrosonography and safety profile. Results: At baseline, the mean number of tender joints (68 count) was 16.2 (± 13.2) and significantly improved to 10.4 (± 11.9) (p = 0.002) at EOT. The mean number of swollen joints (66 count) was reduced from 3.2 (± 3.3) at BL to 1.3 (± 3.2) at EOT (p < 0.001). The disease activity score (DAS28) showed a clinically meaningful decrease over the 16-week period of treatment (p ≤ 0,001). Treatment was well tolerated and adverse events were consistent with the known safety profile of CyA (e.g. hypertension, headache). Conclusion: In this pilot study, promising effects of low-dose CyA treatment on articular involvement were observed in patients with pSS justifying further controlled trials in this indication. No unexpected safety signals were observed. To further investigate the influence of CyA on general health, fatigue, sicca symptoms, longer treatment periods may be necessary

Additional file 1: of A prospective pilot study to evaluate an animated home-based physical exercise program as a treatment option for patients with rheumatoid arthritis

Results of muscle strength measurement (in detail). (XLSX 15 kb