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

Gene-expression analysis of adult-onset Still’s disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity

Background: Adult-onset Still’s disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA). The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset. To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1β inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1β targeting therapy, relative to healthy subjects. Findings: All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects. A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects. Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes. Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients. Conclusions: These results further support the concept of a Still’s disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form

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

Type of vaccine and immunosuppressive therapy but not diagnosis critically influence antibody response after COVID-19 vaccination in patients with rheumatic disease

Objective: The development of sufficient COVID-19 vaccines has been a big breakthrough in fighting the global SARS-CoV-2 pandemic. However, vaccination effectiveness can be reduced in patients with autoimmune rheumatic diseases (AIRD). The aim of this study was to identify factors that lead to a diminished humoral vaccination response in patients with AIRD. Methods: Vaccination response was measured with a surrogate virus neutralisation test and by testing for antibodies directed against the receptor-binding-domain (RBD) of SARS-CoV-2 in 308 fully vaccinated patients with AIRD. In addition, 296 immunocompetent participants were investigated as a control group. Statistical adjusted analysis included covariates with a possible influence on antibody response. Results: Patients with AIRD showed lower antibody responses compared with immunocompetent individuals (median neutralising capacity 90.8% vs 96.5%, p<0.001; median anti-RBD-IgG 5.6 S/CO vs 6.7 S/CO, p<0.001). Lower antibody response was significantly influenced by type of immunosuppressive therapy, but not by rheumatic diagnosis, with patients under rituximab therapy developing the lowest antibody levels. Patients receiving mycophenolate, methotrexate or janus kinase inhibitors also showed reduced vaccination responses. Additional negative influencing factors were vaccination with AZD1222, old age and shorter intervals between the first two vaccinations. Conclusion: Certain immunosuppressive therapies are associated with lower antibody responses after vaccination. Additional factors such as vaccine type, age and vaccination interval should be taken into account. We recommend antibody testing in at-risk patients with AIRD and emphasise the importance of booster vaccinations in these patients

Investigator-initiated clinical trials for evidence based medical reseach in inflammatory rheumatic diseases with articular involvement

Nichtkommerzielle, wissenschaftsgeleitete, Prüfer-initiierte klinische Studien sind gesundheitspolitisch und für die Versorgungspraxis außerordentlich relevant, da sie einerseits eine verzerrte Darstellung der Datenlage (Publikationsbias) korrigieren und andererseits den Patienten neue Perspektiven eröffnen können. Meist sind dabei bereits zugelassene Arzneimittel oder Medizinprodukte Gegenstand der Untersuchung. Pilotstudien, so gennannte Proof-of-Concept (PoC) Studien, stellen dabei ein wertvolles Instrument dar, um erste Hinweise auf die Wirksamkeit oder Praktikabilität aufzudecken. Trotz der Marktzulassung von inzwischen über zwanzig langwirksamen, antirheumatischen Basistherapien muss konstatiert werden, dass sich diese Zulassungen oft auf die rheumatischen Erkrankungen mit der höchsten Prävalenz konzentrieren. Seltene Erkrankungen wie das primäre Sjögren Syndrom oder das noch seltenere Still Syndrom des Erwachsenen bleiben bei der pharmazeutischen Entwicklung häufig unberücksichtigt. Selbst bei der rheumatoiden Arthritis, der rheumatisch-entzündlichen Erkrankung mit der höchsten Prävalenz, gibt es heutzutage zwar viele medikamentösen Behandlungsoptionen, es besteht jedoch ein Bedarf an ergänzenden nicht- pharmakologischen, physikalischen Therapieoptionen zum Erhalt der Gelenkfunktion. Im Rahmen dieser Publikationspromotion werden die Ergebnisse aus drei klinischen PoC-Studien zusammengefasst, welche den Einsatz von zwei bewährten, zugelassenen rheumatologischen Basistherapien in anderen Indikationen untersuchten, sowie erste Evidenzen zur Machbarkeit und Wirksamkeit einer komplementären nicht-medikamentösen Intervention sammelten. Die Analyse zeigte vielversprechende Effekte einer niedrig dosierten Cyclosporin A Behandlung hinsichtlich der Verbesserung der artikulären Beschwerden bei Patienten mit primärem Sjögren Syndrom und Gelenkbeteiligung. Ferner belegen die Ergebnisse der zweiten Pilotstudie eine Machbarkeit und einen Nutzen eines animierten Übungsprogramms mittels einer frei verkäuflichen Spielkonsole für Patienten mit rheumatoider Arthritis. In einer dritten, multizentrischen Pilotstudie trugen Ergebnisse einer Substudie, die sich mit molekularbiologischen Grundlagen beschäftigte (Genexpressionsanalyse), zu einer Zulassungserweiterung des Wirkstoffs Canakinumab zur Behandlung des Still-Syndroms des Erwachsenen bei. Zusammengefasst ergaben diese Pilotstudien positive Ergebnisse für Patienten mit entzündlich-rheumatischen Erkrankungen und Gelenkbeteiligung und rechtfertigen weitere kontrollierte Studien in den untersuchten Indikationen. Sie unterstreichen die besondere Bedeutung der nichtkommerziellen, wissenschaftsgeleiteten, Prüfer-initiierten klinischen Studien für die evidenzbasierte medizinische Forschung.Non-commercial, science-based and investigator-initiated clinical trials play an important role in health policy and medical care. They may reduce publication bias and open up new perspectives for patients. In the majority of these trials, approved drugs or medical devices are the objects of investigations. In this context, pilot studies (Proof-of-Concept studies, PoC) are feasible and valuable instruments in order to obtain initial evidence for efficacy and/or practicability. More than 20 disease modifying anti-rheumatic drugs (DMARD’s) have already received marketing authorization, however, the majority of these medications has been approved for rheumatic diseases with the highest prevalence. Rheumatic diseases like the primary Sjögren’s syndrome (pSS) and the rare disease adult onset Still disease (AOSD) have been not in the focus of new pharmacological development so far. Even in rheumatoid arthritis (RA), as a rheumatic disease with a prevalence of 0.5 – 1% and good treatment options, an unmet medical need still excists. This includes a high proportion of RA patients with loss of physical function despite intake of effective DMARDs. Therefore, non-pharmacological, physical interventions are of high importance as adjunctive therapy to pharmacologic treatment. This dissertation summarizes the results of three PoC-studies investigating two approved DMARD’s in other medical indications as well as a complementary, non- pharmacological intervention. As a result, promising effects were observed for low-dose Cyclosporine A treatment on articular involvement in patients with pSS. The second pilot study showed that an animated home-based exercise program by using a game console was feasible and beneficial for RA patients. The results of a fundamental molecular biological subanalysis (gene epression profiling) of the third, multicentre pilot study supported a conditional marketing authorization of canakinumab for the treatment of AOSD. In summary, these pilot studies showed positive results for patients with inflammatory rheumatic diseases with articular involvement justifying further controlled trials in these indications. The results obtained underline the particular importance of non-commercial, science-based, investigator-driven clinical trials in the evidence-based medical research

Additional file 2: of A prospective pilot study to evaluate an animated home-based physical exercise program as a treatment option for patients with rheumatoid arthritis

Patient reported outcomes (questionnaires). (DOCX 746 kb

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