Patient Reported Outcomes in Chronic Inflammatory Diseases: Current State, Limitations and Perspectives

Chronic inflammatory diseases (CID) are emerging disorders which do not only affect specific organs with respective clinical symptoms but can also affect various aspects of life, such as emotional distress, anxiety, fatigue and quality of life. These facets of chronic disease are often not recognized in the therapy of CID patients. Furthermore, the symptoms and patient-reported outcomes often do not correlate well with the actual inflammatory burden. The discrepancy between patient-reported symptoms and objectively assessed disease activity can indeed be instructive for the treating physician to draw an integrative picture of an individual's disease course. This poses a challenge for the design of novel, more comprehensive disease assessments. In this mini-review, we report on the currently available patient-reported outcomes, the unmet needs in the field of chronic inflammatory diseases and the challenges of addressing these

Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo.

In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory

The role of long-lived plasma cells in autoimmunity

Ein großer Teil der systemischen Autoimmunerkrankungen ist nachweislich an das Vorhandensein von Antikörpern gegen definierte Autoantigene gekoppelt. Diese Autoantikörper werden von den end-differenzierten Stadien der B-Zell- Linie, den sogenannten Plasmazellen, produziert und sezerniert. In der Vergangenheit konnten wir gezeigt werden, dass es bei den Plasmazellen mindestens zwei Untergruppen gibt: die sogenannten kurzlebigen Plasmazellen und die langlebigen Gedächtnis-Plasmazellen. Die Gedächtnis-Plasmazellen haben eine beträchtlich längere Lebensdauer als kurzlebige Zellen (Jahre vs. Tage). Sie proliferieren nicht mehr und sezernieren kontinuierlich spezifische Antikörper. Wir konnten erstmals zeigen, dass dies auch in einem hyperaktivierten Immunsystem, wie dies im Mausmodell des systemischen Lupus Erythematodes zu finden ist, der Fall ist. Sowohl unter den kurzlebigen als auch unter den Gedächtnis- Plasmazellen finden sich pathogene autoreaktive Zellen. Das Gedächtnis- Plasmazellkompartiment entsteht lange vor Ausbruch der klinischen Krankheitssymptome und ihre Neugeneration hält die komplette Lebenszeit an. Eine kombinierte Depletion der Plasmazellen und ihrer Vorläufer führt zu einer persistierenden Immunablation. Die Population autoreaktiver Gedächtnis- Plasmazellen stellt eine therapeutische Herausforderung dar. Standard- Immunsuppressiva sind nicht in der Lage, diese Zellen zu eliminieren. So tragen die Gedächtnis-Plasmazellen dazu bei, dass trotz massiver Immunsuppression Patienten bisher nicht geheilt werden können. Beim Patienten mit unterschiedlichen Autoimmunerkrankungen findet sich im Zusammenhang mit einem Krankheitsschub eine Expansion von kurzlebigen Plasmablasten im Blut als Korrelat für die systemische B-Zell- Hyperaktivierung. Dies ist, neben dem Nachweis von Autoantikörpern, ein Hinweis für eine Rolle der Plasmazellen in der Pathogenese der Erkrankungen. Bisher sind wir nur zu einer unspezifischen Immunsuppression in der Lage. Mit Hilfe der Matrix-Technologie ist eine spezifische Depletion von Plasmazellen einer definierten Spezifität möglich. Für eine Übertragung der murinen Daten in die Klinik ist ein noch besseres Verständnis der Rolle und Funktion der Plasmazellen bei unterschiedlichen Autoimmunerkrankungen Voraussetzung. Dies würde einen Durchbruch in der Therapie aller chronischen Antikörper- vermittelten Erkrankungen, auch außerhalb der Rheumatologie, bedeuten.Systemic autoimmunity is often enough linked tot he presence of autoantibodies against specific antigens. Terminally differentiated B cells, the so-called plasma cells, secrete these antibodies. We could show in the past that plasma cells can be divided into at least two subpopulations: short-lived plasmablasts and plasma cells and long-lived memory plasma cells. Memory plasma cells do have a considerably extended lifespan as compared to short- lived plasma cells (years vs. days). They are non-proliferating and permanently secrete antibodies. We could show that even in the hyperactive immune system that can be found in systemic lupus erythematosus, memory plasma cells are present. Within both plasma cell populations pathogenic autoreactive cells can be detected. The memory plasma cell compartment is established long before first symptoms of the disease are visible and the regeneration of cells continues throughout life. A combined depletion of plasma cells and their precursors leads to persistent immunoablation. The population of autoreactive memory plasma cells can be considered as a therapeutic challenge as conventional therapies are not able to deplete them. This is one oft he reasons why to the day we are not able to „cure“ autoimmunity. In patients with a variety of autoimmune diseases plasma cell expansion can be detected in the blood in the context of increased disease activity. These cells are short- lived plasma cells considered as a correlate for systemic B cell hyperactivity. In addition to the presence of autoantibodies this indicates a role of plasma cells in the pathogenesis of the diseases. Until now, immunosuppression to treat autoimmunity was always unselective and unspecific. Using the matrix technology we could fort he first time, selectively deplete plasma cells of a certain specificity. For translating this technology into the clinic an even better understanding oft he role and function of plasma cells in autoimmunity is needed. This could lead to the needed break-through in treating chronic autoantibody-mediated autoimmune diseases

Humoral protection to SARS-CoV2 declines faster in patients on TNF alpha blocking therapies

Background The persistence of the SARS-CoV2 pandemic, partly due to the appearance of highly infectious variants, has made booster vaccinations necessary for vulnerable groups. Questions remain as to which cohorts require SARS-CoV2 boosters. However, there is a critical lack of data on the dynamics of vaccine responses in patients with chronic inflammatory diseases (CID) undergoing immunosuppressive/disease modifying anti-rheumatic (DMARD) treatment. Here, we present the first data regarding the decline of the vaccine-induced humoral immune responses in patients with CID. Methods 23 patients with CID were monitored clinically and for anti-spike IgG and IgA levels, neutralization efficacy and antigen-specific CD4+ T cell responses over the first 6 months after SARS-CoV2 vaccination. 24 healthy individuals were included as controls. Results While anti-spike IgG-levels declined in CID patients and healthy controls, patients receiving anti-TNF treatment showed significantly greater declines at 6 months post second vaccination in IgG and especially neutralizing antibodies. IgA levels were generally lower in CID patients, particularly during anti-TNF therapy. No differences in SARS-CoV2 spike-specific CD4+ T-cell frequencies were detected. Conclusion Although the long-term efficacy of SARS-CoV2 vaccination in CID patients undergoing disease-modifying therapy is still not known, the pronounced declines in humoral responses towards SARS-CoV2 6 months after mRNA vaccination in the context of TNF blockade should be considered when formulating booster regimens. These patients should be considered for early booster vaccinations

Deutsches Register www.Covid19-Rheuma.de

The COVID-19 registry ( www.covid19-rheuma.de ) of the German Society of Rheumatology was the first registry for the acquisition and systemic evaluation of viral infections in patients with inflammatory rheumatic diseases (IRD). This has enabled rapid generation of scientific data that will help to improve the care of patients with IRD in the context of the pandemic. In addition to confirming general risk factors, such as patient age and comorbidities (e.g. cardiovascular, chronic lung and kidney diseases), the use of glucocorticoids and the disease activity of the rheumatic disease could be identified as disease-specific independent risk factors for the need of hospitalization due to COVID-19. Evaluations of the continuously growing cohort of patients with IRD and COVID-19 enable recommendations for patient care to be based on better evidence. Cooperation with international rheumatology registries (e.g. European COVID-19 registry for IRD) enables analyses of aggregated cohorts of patients with IRD and COVID-19 for international comparisons and statistically even more reliable statements

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options.Peer reviewe

Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19.

Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P < .001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P = .004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P = .33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs

Characteristics and outcomes of SARS-CoV-2 breakthrough infections among double-vaccinated and triple-vaccinated patients with inflammatory rheumatic diseases

Objective To analyse the clinical profile of SARS-CoV-2 breakthrough infections in at least double-vaccinated patients with inflammatory rheumatic diseases (IRDs).Methods Data from the physician-reported German COVID-19-IRD registry collected between February 2021 and July 2022 were analysed. SARS-CoV-2 cases were stratified according to patients’ vaccination status as being not vaccinated, double-vaccinated or triple-vaccinated prior to SARS-CoV-2 infection and descriptively compared. Independent associations between demographic and disease features and outcome of breakthrough infections were estimated by multivariable logistic regression.Results In total, 2314 cases were included in the analysis (unvaccinated n=923, double-vaccinated n=551, triple-vaccinated n=803, quadruple-vaccinated n=37). SARS-CoV-2 infections occurred after a median of 151 (range 14–347) days in patients being double-vaccinated, and after 88 (range 14–270) days in those with a third vaccination. Hospitalisation was required in 15% of unvaccinated, 8% of double-vaccinated and 3% of triple-vaccinated/quadruple-vaccinated patients (p&lt;0.001). Mortality was 2% in unvaccinated, 1.8% in the double-vaccinated and 0.6% in triple-vaccinated patients. Compared with unvaccinated patients, double-vaccinated (OR 0.43, 95% CI 0.29 to 0.62) and triple-vaccinated (OR 0.13, 95% CI 0.08 to 0.21) patients showed a significant lower risk of COVID-19-related hospitalisation. Using multivariable analysis, the third vaccination was significantly associated with a lower risk for COVID-19-related death (OR 0.26; 95% CI 0.01 to 0.73).Conclusions Our cross-sectional data of COVID-19 infections in patients with IRD showed a significant reduction of hospitalisation due to infection in double-vaccinated or triple-vaccinated patients compared with those without vaccination and even a significant reduction of COVID-19-related deaths in triple-vaccinated patients. These data strongly support the beneficial effect of COVID-19 vaccination in patients with IRD.Trial registration number EuDRACT 2020-001958-21