Publications by authors named "Bernhard Hellmich"

60 Publications

[Biologics for connective tissue diseases and vasculitides].

Internist (Berl) 2022 Jan 14. Epub 2022 Jan 14.

Zentrum für Interdisziplinäre Klinische Immunologie, Rheumatologie und Autoimmunerkrankungen (INDIRA), Universitätsklinikum Tübingen, Tübingen, Deutschland.

Despite therapy with glucocorticoids (GC) and conventional immunosuppressants, patients with connective tissue diseases and vasculitides often develop functionally relevant and prognostically unfavourable internal organ damage. Based on new pathogenetic insights, biologics and small molecules have recently been studied as targeted therapies for collagen vascular diseases and vasculitides. The B lymphocyte stimulator antagonist belimumab has been used for the treatment of systemic lupus erythematosus (SLE) for several years and has recently also been approved as an add-on therapy for lupus nephritis. Anifrolumab, an antibody against the type‑1 interferon receptor, has also been shown to be effective in phase III trials for the treatment of SLE. The interleukin (IL)-6-antagonist tocilizumab showed efficacy in the treatment of interstitial lung disease (ILD) in systemic sclerosis (SSc) and thus has been approved in the USA, although the phase III trial had a negative primary endpoint. In Europe the tyrosine inhibitor nintedanib is approved for progressive ILD in SSc. Tocilizumab is approved for the treatment of giant cell arteritis and reduces both the risk of recurrence and the cumulative GC requirement. The B‑lymphocyte depleting antibody rituximab is approved for induction and maintenance therapy of granulomatosis with polyangiitis and microscopic polyangiitis (MPA) and is currently also being investigated for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). In patients with EGPA, the IL‑5 antibody mepolizumab leads to improved disease control and reduces GC requirements. A phase III trial of the small molecule antagonist avacopan targeting the complement C5a receptor as a replacement for high-dose GC in induction therapy of GPA and MPA met its primary endpoints. Various other biologics and small molecule antagonists are currently in clinical development for several type of vasculitis and collagen vascular diseases, some of them at advanced stages.
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http://dx.doi.org/10.1007/s00108-021-01249-wDOI Listing
January 2022

Management of nonviral mixed cryoglobulinemia vasculitis refractory to rituximab: Data from a European collaborative study and review of the literature.

Autoimmun Rev 2022 Jan 4;21(4):103034. Epub 2022 Jan 4.

Department of Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France. Electronic address:

Background: Glucocorticoids (GCs) plus rituximab (RTX) represent the first-line treatment of nonviral mixed cryoglobulinemia vasculitis (CryoVas). However, data on therapeutic management and outcome of patients refractory to RTX are lacking.

Methods: We conducted a European collaborative retrospective multicenter study of patients with nonviral mixed CryoVas refractory to RTX and performed a literature review.

Results: Twenty-six original cases and 7 additional patients from the literature were included. All patients but one had type 2 cryoglobulinemia, and causes were autoimmune disease (51%), malignant hemopathy (12%) or essential CryoVas (42%). CryoVas was primary refractory to RTX in 42%, while 58% had an initial response to RTX before immune escape. After RTX failure, patients received a median of 1 (IQR, 1-3) line of treatment, representing 65 treatment periods during follow-up. Main treatments used were GCs in 92%, alkylating agents in 43%, RTX in combination with other treatments in 46%, and belimumab in 17%. Combination of anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents provided the highest rates of clinical response in 100% 82% and 73%, respectively, but showed poor immunological response, in 50%, 30% and 38%, respectively. Rates of severe infection were 57%, 9% and 0% in patients receiving anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents, respectively.

Conclusion: In patients with nonviral mixed CryoVas refractory to RTX, anti-CD20 plus belimumab, and alkylating agents associated or not with anti-CD20, provide the highest rates of clinical response. However, anti-CD20 plus belimumab was frequently associated with severe infections.
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http://dx.doi.org/10.1016/j.autrev.2022.103034DOI Listing
January 2022

[Diagnostics and treatment of giant cell arteritis].

Nervenarzt 2021 Nov 3. Epub 2021 Nov 3.

Klinik für Innere Medizin, Rheumatologie und Immunologie, Medius-Klinik Kirchheim unter Teck, Kirchheim unter Teck, Deutschland.

Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in the age group over 50 years. It requires prompt diagnostics and treatment to avoid severe complications, such as visual loss or stroke. The tendency to relapse makes a glucocorticoid (GC) treatment necessary for several years and sometimes lifelong, which increases the risk of GC-induced long-term side effects. Therefore, additive GC-sparing treatment is recommended in the majority of patients. For this purpose, the anti-IL‑6 receptor antibody tocilizumab is available as an approved substance for subcutaneous application; alternatively, methotrexate (MTX) can be used (off-label).
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http://dx.doi.org/10.1007/s00115-021-01216-8DOI Listing
November 2021

GCA management guidelines - vive la différence?

Nat Rev Rheumatol 2021 11;17(11):649-650

Medizinische Klinik m. S. Rheumatologie und Klinische Immunologie, Charité Universitätsmedizin Berlin (CCM), Berlin, Germany.

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http://dx.doi.org/10.1038/s41584-021-00686-zDOI Listing
November 2021

Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: A European Multicenter Observational Study.

Arthritis Rheumatol 2021 Aug 4. Epub 2021 Aug 4.

San Giovanni Bosco Hospital and University of Turin, Turin, Italy.

Objective: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real-life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort.

Methods: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015-2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ≤4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations.

Results: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty-five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty-two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44).

Conclusion: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial.
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http://dx.doi.org/10.1002/art.41943DOI Listing
August 2021

The Joint Vasculitis Registry in German-speaking countries (GeVas) - a prospective, multicenter registry for the follow-up of long-term outcomes in vasculitis.

BMC Rheumatol 2021 Jul 31;5(1):40. Epub 2021 Jul 31.

Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany.

Background: Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective - studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period.

Methods: GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future.

Discussion: In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period.

Trial Registration: German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866 . Registered 10 May 2019.
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http://dx.doi.org/10.1186/s41927-021-00206-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325211PMC
July 2021

[Glucocorticoids in the treatment of giant cell arteritis : How much, how long and how to spare?]

Z Rheumatol 2021 May 12;80(4):322-331. Epub 2021 Mar 12.

Vaskulitiszentrum Süd, Klinik für Innere Medizin, Rheumatologie und Immunologie, Medius Kliniken - Akademisches Lehrkrankenhaus der Universität Tübingen, Eugenstr. 3, 73230, Kirchheim unter Teck, Deutschland.

Treatment of giant cell arteritis (GCA) with high-dose glucocorticoids (GC) regularly leads to a control of the inflammatory activity, so that high-dose GC is still the recommended standard treatment in the current guidelines; however, after discontinuation of GC treatment or reduction of the GC dosage, relapses occur in up to 70% of patients in the further course of the disease, making it necessary to resume treatment or increase the dosage. As a consequence many patients therefore have to be treated with GC often in high doses over several years, which results in a high cumulative exposure to GC. The risk for GC-associated diseases, such as diabetes, glaucoma, osteoporosis or severe infections is therefore significantly increased for patients with giant cell arteritis. For patients with GC-associated comorbidities or increased risk of developing them or patients with a relapse, the current guidelines therefore recommend GC-sparing treatment with tocilizumab or alternatively methotrexate. It is currently unclear over what period of time patients should be treated with GC and GC-sparing treatment, since high-quality study data on de-escalation strategies for GCA are currently still lacking. Decisions on treatment duration and intensity must therefore be made individually for each patient, taking into account general and patient-specific risk factors for a GC-dependent course, GCA-associated vascular damage (stenoses, aneurysms, visual loss) and treatment-associated complications.
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http://dx.doi.org/10.1007/s00393-021-00975-8DOI Listing
May 2021

New insights into the epidemiology of ANCA-associated vasculitides in Germany: results from a claims data study.

Rheumatology (Oxford) 2021 10;60(10):4868-4873

Vifor Fresenius Medical Care Renal Pharma, Glattbrugg, Switzerland.

Objective: ANCA-associated vasculitides (AAV) are rare, potentially life-threatening autoimmune diseases characterized by systemic inflammation and organ damage. AAV prevalence rates reported in Europe vary considerably and robust data sources are often lacking. This study aimed to examine the feasibility of claims data analysis as a complementary method to registry-based studies to assess the epidemiology of AAV.

Methods: In this retrospective observational study, anonymized longitudinal claims data from years 2013-2016 from German statutory health insurance companies (data source: InGef, Institute for Applied Health Research) have been analysed on an age- and gender-stratified cohort of ∼3 million persons representative of the German population. In this cohort, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients were identified.

Results: The study cohort revealed a prevalence for GPA and MPA of 210 and 46 cases per million people, respectively. The annual incidence comprised 34 GPA cases and 13 MPA cases per million people per year. Hence, 17 500 AAV patients (GPA and MPA) are estimated to live in Germany, with an annual increase of 3200 patients. According to their demographic and disease-specific characteristics, AAV patients identified in this claims data approach are representative.

Conclusion: This is the first study using claims data to assess the epidemiology of AAV. In Germany, AAV was diagnosed more frequently than it was estimated by previous self-reporting registry-based studies. The findings indicate that epidemiological data of AAV may have been underestimated but may also reflect improved diagnostic methods and disease recognition.
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http://dx.doi.org/10.1093/rheumatology/keaa924DOI Listing
October 2021

Significance of PR3-ANCA positivity in eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

Rheumatology (Oxford) 2021 09;60(9):4355-4360

Department of Internal Medicine, Cochin Hospital, National Referral Center for Rare Systemic Autoimmune Diseases, Paris University, Paris, France.

Objectives: Only a third of patients with eosinophilic granulomatosis with polyangiitis (EGPA) are ANCA-positive, mainly directed against MPO. ANCA directed against PR3 are rarely found in EGPA. We aimed to examine the significance of PR3-ANCA in EGPA.

Methods: We set up a retrospective European multicentre cohort including 845 patients. Baseline characteristics and outcomes were analysed and compared according to ANCA status.

Results: ANCA status was available for 734 patients: 508 (69.2%) ANCA-negative, 210 (28.6%) MPO-ANCA and 16 (2.2%) PR3-ANCA. At baseline, PR3-ANCA patients, compared with those with MPO-ANCA and ANCA-negative, less frequently had active asthma (69% vs 91% and 93%, P = 0.003, respectively) and peripheral neuropathy (31% vs 71% and 47%, P < 0.0001), more frequently had cutaneous manifestations (63% vs 38% and 34%, P = 0.03) and pulmonary nodules (25% vs 10% and 8%, P = 0.046), and lower median eosinophil count (1450 vs 5400 and 3224/mm3, P < 0.0001). Vasculitis relapse-free survival was shorter for PR3-ANCA (hazard ratio 6.05, P = 0.005) and MPO-ANCA patients (hazard ratio 1.88, P = 0.0002) compared with ANCA-negative patients.

Conclusion: PR3-ANCA EGPA patients differ from those with MPO-ANCA and negative ANCA, and share clinical features with granulomatosis with polyangiitis. This suggests that PR3-ANCA EGPA could be a particular form of PR3-ANCA-associated vasculitis.
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http://dx.doi.org/10.1093/rheumatology/keaa805DOI Listing
September 2021

Evaluation of PR3- and MPO-ANCA line and dot immunoassays in ANCA-associated vasculitis.

Rheumatology (Oxford) 2021 09;60(9):4390-4394

Rheumatologie und Immunologie, Klinik für Innere Medizin, Medius Klinik Kirchheim, Akademisches Lehrkrankenhaus der Universität Tübingen, Kirchheim unter Teck, Germany.

Objective: This study was performed to evaluate the diagnostic accuracy of novel line and dot immunoassays for detection of MPO and PR3 ANCA.

Methods: Sera from 50 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 45 disease controls were tested by IIF and for the presence of PR3-ANCA and MPO-ANCA by four different line or dot immunoassays, as well as by a chemiluminescence immunoassay.

Results: The area under the curve of the receiver operating characteristic curve to discriminate AAV from controls was 0.858 (95% CI 0.785-0.931) for the IIF method. For the antigen-specific immunoassays, the area under the curve varied between 0.869 (95% CI 0.797-0.941) and 0.936 (95% 0.886-0.985).

Conclusions: Our comparison of various ANCA detection methods showed a high degree of diagnostic precision for all of the PR3- and MPO-ANCA line and dot immunoassays investigated. The performance was equal to or better than the performance of IIF. These results indicate that novel line and dot immunoassays can serve as a first-line test method in patients with the suspected diagnosis of AAV.
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http://dx.doi.org/10.1093/rheumatology/keaa776DOI Listing
September 2021

[Large vessel vasculitis].

Z Rheumatol 2020 Aug;79(6):503-504

Rheumazentrum Schleswig-Holstein Mitte, Kuhberg 5a-7, 24534, Neumünster, Deutschland.

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http://dx.doi.org/10.1007/s00393-020-00810-6DOI Listing
August 2020

Two Immunocompromised Patients With Diffuse Alveolar Hemorrhage as a Complication of Severe Coronavirus Disease 2019.

Chest 2020 11 2;158(5):e215-e219. Epub 2020 Jul 2.

Department of Internal Medicine, Rheumatology and Immunology, medius Klinik Kirchheim, Academic Teaching Hospital University of Tübingen, Kirchheim unter Teck, Germany.

Diffuse alveolar hemorrhage (DAH) is a severe and potentially life-threatening disease manifestation. In addition to autoimmune diseases such as antineutrophil cytoplasmic antibody-associated vasculitis and anti-glomerular basement membrane syndrome, pulmonary viral infections are known to be culprits of DAH. Health-care providers worldwide in the coronavirus disease 2019 pandemic have been confronted with an unprecedented number of viral lung infections, with great variance in symptoms and severity. Hemoptysis, the key symptom of DAH, is a rare complication. We present two cases of immunocompromised patients with rapidly developing hypoxemic respiratory failure and evidence of DAH in the context of severe acute respiratory syndrome coronavirus 2 infection.
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http://dx.doi.org/10.1016/j.chest.2020.06.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331533PMC
November 2020

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

Am J Respir Crit Care Med 2020 Jun 25. Epub 2020 Jun 25.

University of Alberta, Medicine, Edmonton, Alberta, Canada.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work‑up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.
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http://dx.doi.org/10.1164/rccm.202005-1628SODOI Listing
June 2020

Usefulness of vasculitis biomarkers in the era of the personalized medicine.

Autoimmun Rev 2020 May 12;19(5):102514. Epub 2020 Mar 12.

Klinik für Innere Medizin - Rheumatologie und Immunologie, Medius Klinik Kirchheim, Akademisches Lehrkrankenhaus der Universität Tübingen, Germany.

In recent years, insight into immune pathogenesis and treatment of primary systemic vasculitides (PSV) has increased considerably, and has led to the development of many clinically relevant biomarkers. This review aims to provide an update on the main biomarkers discovered and their potential application to precision medicine in vasculitis. Genetic and molecular profiling of patients and promising biomarkers discoveries are very important for personalized medicine; however, there are very limited data in PSV. Genetic studies including mainly genome-wide association studies (GWAS) had led to important discoveries in disease pathogenesis of PSV while whole exome sequencing studies lead to discovery of monogenic vasculitides. Although there are numerous studies addressing novel biomarkers in PSV, few of these biomarkers are currently being used in routine clinical practice in the management of patients with PSV. Current studies indicate that ANCA types identify distinct prognostic subsets of ANCA vasculitis patients. Today, biomarkers-driven treatment algorithms are not available in PSV.
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http://dx.doi.org/10.1016/j.autrev.2020.102514DOI Listing
May 2020

[Anti B-cell-antibody treatment for maintenance of remission in granulomatosis with polyangiitis and microscopic polyangiitis].

Dtsch Med Wochenschr 2020 01 8;145(1):40-46. Epub 2020 Jan 8.

Klinik für Rheumatologie und Klinische Immunologie, Department Innere Medizin, Medizinische Fakultät, Universitätsklinikum Freiburg, Freiburg.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most frequent primary necrotizing small vessel vasculitides. In these formerly fatal diseases remission can be induced by stage- and activity-adapted immunosuppressive regimens in the majority of patients. This does not lead to drug-free long-term remission or even cure. Consequently, maintenance of remission medication is needed. Recent randomized controlled trials demonstrated that maintenance treatment with the anti-B-cell antibody Rituximab, administered 6-monthly as opposed to azathioprine leads to a significantly lower relapse rate but a similar profile of adverse events. These data enabled the extension of the approval of Rituximab for maintenance of remission treatment of GPA and MPA in Germany in 2018. Guidelines and expert recommendations concerning measures of infection prevention and vaccination of immunosuppressed patients as well as the management of hypogammaglobulinemia and cytopenia on Rituximab are presented in this review.
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http://dx.doi.org/10.1055/a-1060-2736DOI Listing
January 2020

Management of Takayasu arteritis: a systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis.

RMD Open 2019 23;5(2):e001020. Epub 2019 Sep 23.

Klinik für Innere Medizin, Rheumatologie und Immunologie, Vaskulitis-Zentrum Süd, Medius Kliniken, - Akademisches Lehrkrankenhaus der Universität Tübingen, Kirchheim-unter-Teck, Germany.

Objective: To collect available evidence on management of large vessel vasculitis to inform the 2018 update of the EULAR management recommendations.

Methods: Two independent systematic literature reviews were performed, one on diagnosis and monitoring and the other on drugs and surgical treatments. Using a predefined PICO (population, intervention, comparator and outcome) strategy, Medline, Embase and Cochrane databases were accessed. Eligible papers were reviewed and results condensed into a summary of findings table. This paper reports the main results for Takayasu arteritis (TAK).

Results: A total of 287 articles were selected. Relevant heterogeneity precluded meta-analysis. Males appear to have more complications than females. The presence of major complications, older age, a progressive disease course and a weaker inflammatory response are associated with a more unfavourable prognosis. Evidence for details on the best disease monitoring scheme was not found. High-quality evidence to guide the treatment of TAK was not found. Glucocorticoids are widely accepted as first-line treatment. Conventional immunosuppressive drugs and tumour necrosis factor inhibitors were beneficial in case series and uncontrolled studies. Tocilizumab failed the primary endpoint (time to relapse) in a randomised controlled clinical trial; however, results still favoured tocilizumab over placebo. Vascular procedures may be required, and outcome is better when performed during inactive disease.

Conclusions: Evidence to guide monitoring and treatment of patients with TAK is predominantly derived from observational studies with low level of evidence. Therefore, higher-quality studies are needed in the future.
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http://dx.doi.org/10.1136/rmdopen-2019-001020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803017PMC
April 2020

Systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis: focus on giant cell arteritis.

RMD Open 2019 16;5(2):e001003. Epub 2019 Sep 16.

Klinik für Innere Medizin, Rheumatologie und Immunologie, Vaskulitis-Zentrum Süd, Medius Kliniken, Universitatsklinikum Tubingen, Tubingen, Germany.

Objectives: To analyse the current evidence for the management of large vessel vasculitis (LVV) to inform the 2018 update of the EULAR recommendations.

Methods: Two systematic literature reviews (SLRs) dealing with diagnosis/monitoring and treatment strategies for LVV, respectively, were performed. Medline, Embase and Cochrane databases were searched from inception to 31 December 2017. Evidence on imaging was excluded as recently published in dedicated EULAR recommendations. This paper focuses on the data relevant to giant cell arteritis (GCA).

Results: We identified 287 eligible articles (122 studies focused on diagnosis/monitoring, 165 on treatment). The implementation of a fast-track approach to diagnosis significantly lowers the risk of permanent visual loss compared with historical cohorts (level of evidence, LoE 2b). Reliable diagnostic or prognostic biomarkers for GCA are still not available (LoE 3b).The SLR confirms the efficacy of prompt initiation of glucocorticoids (GC). There is no high-quality evidence on the most appropriate starting dose, route of administration, tapering and duration of GC (LoE 4). Patients with GCA are at increased risk of dose-dependent GC-related adverse events (LoE 3b). The addition of methotrexate or tocilizumab reduces relapse rates and GC requirements (LoE 1b). There is no consistent evidence that initiating antiplatelet agents at diagnosis would prevent future ischaemic events (LoE 2a). There is little evidence to guide monitoring of patients with GCA.

Conclusions: Results from two SLRs identified novel evidence on the management of GCA to guide the 2018 update of the EULAR recommendations on the management of LVV.
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http://dx.doi.org/10.1136/rmdopen-2019-001003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803016PMC
April 2020

2018 Update of the EULAR recommendations for the management of large vessel vasculitis.

Ann Rheum Dis 2020 01 3;79(1):19-30. Epub 2019 Jul 3.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMs), University of Oxford, Oxford, UK.

Background: Since the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations.

Methods: Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations.

Results: Three overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40-60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons.

Conclusions: We have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice.
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http://dx.doi.org/10.1136/annrheumdis-2019-215672DOI Listing
January 2020

[Eosinophilic diseases in rheumatology].

Z Rheumatol 2019 May;78(4):304-305

Rheumazentrum Schleswig-Holstein Mitte, Kuhberg 5a-7, 24534, Neumünster, Deutschland.

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http://dx.doi.org/10.1007/s00393-019-0614-yDOI Listing
May 2019

Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease.

Ann Rheum Dis 2018 06 22;77(6):840-847. Epub 2018 Feb 22.

AB2 Bio Ltd, EPFL Innovation Park, Lausanne, Switzerland.

Objectives: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD.

Methods: In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study.

Results: Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria.

Conclusions: Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD.

Trial Registration Number: NCT02398435.
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http://dx.doi.org/10.1136/annrheumdis-2017-212608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965361PMC
June 2018

Anti-neutrophil cytoplasm antibodies (ANCA): Recent methodological advances-Lead to new consensus recommendations for ANCA detection.

J Immunol Methods 2018 05 31;456:1-6. Epub 2018 Jan 31.

Department of Internal Medicine, Rheumatology and Immunology, Vasculitis-Center Tübingen-Kirchheim, Medius Klinik Kirchheim, University of Tübingen, Kirchheim-Teck, Germany. Electronic address:

The current practice for detection of anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) and myeloperoxidase (MPO) has been screening by indirect immunofluorescence (IIF) followed by an antigen specific tests for PR3- and MPO-ANCA. However, ANCA diagnostics have undergone many technical developments that have affected the 1999 international consensus recommendations, and lead to a revision of the existing ANCA detection strategy. Recent European multicentre studies have compared the diagnostic performance of various ANCA detection methods and demonstrated that PR3- and MPO-ANCA immunoassays yielded the highest diagnostic accuracy. New guidelines for ANCA testing have been developed based on these data. According to the revised 2017 international consensus recommendations, testing for ANCA in small vessel vasculitis can be done by PR3- and MPO-ANCA immunoassays, without the categorical need for IIF. Thus, IIF can be discarded completely, or can be used as confirmation assays instead a screening test. Clearly, though, the new testing strategy for ANCA in vasculitis must identify the ANCA target antigen, as PR3- and MPO-ANCA serotype correlate well with disease expression. Furthermore, recent studies have shown that AAV can be classified based on ANCA serotype, since PR3- and MPO-ANCA- diseases are strongly associated with distinguishable genetic alleles, different clinical and histological features. ANCA presence and the antigen specificity also may have important value as a prognostic factor and may serve as a guide for immunosuppressive therapy. In the current review, we summarize the novelties in ANCA testing, present the 2017 revised international consensus on ANCA testing in vasculitis, evaluate the diagnostic significance of ANCA, and discuss the role of ANCA serotypes in the diagnostic work-up of patients with AAV.
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http://dx.doi.org/10.1016/j.jim.2018.01.007DOI Listing
May 2018

Validation of the EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis by disease content experts.

RMD Open 2017 15;3(1):e000449. Epub 2017 Jun 15.

Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK.

The European League Against Rheumatism recommendations for the management of antineutrophil cytoplasmic antibody-associated vasculitis have been recently published. Unique to recommendation development, they were also voted on by members of a learned society. This paper explores the wider validity of the recommendations among people who self-identify as clinicians caring for patients with vasculitis. In addition to the task force, a learned society (European Vasculitis Society-EUVAS) was invited, through online survey, to rate independently the strength of evidence of each recommendation to obtain an indication of the agreement among the final target audience and ultimate end-users of the recommendations. The survey took place in June 2015. Of the 158 EUVAS members surveyed, there were 88 responses (55.7%). There was a large degree of agreement in the voting patterns between EUVAS survey participants and task force members. Notable exceptions were lower grades for the recommendation of the use of rituximab for remission induction in patients with eosinophilic granulomatosis with polyangiitis and for methotrexate and mycophenolate mofetil as remission maintenance agents in patients with granulomatosis with polyangiitis/microscopic polyangiitis by EUVAS members. These results are encouraging and suggest that the voting patterns of the task force are representative of the wider vasculitis community. We recommend future recommendations adopt this approach for data/expert-based treatment guidelines, especially for multisystem diseases.
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http://dx.doi.org/10.1136/rmdopen-2017-000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604609PMC
June 2017

Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis.

Nat Rev Rheumatol 2017 Nov 14;13(11):683-692. Epub 2017 Sep 14.

Department of Internal Medicine, Rheumatology and Immunology, Vasculitis-Centre Tübingen-Kirchheim, Medius Klinik Kirchheim, University of Tübingen, Eugenstrasse 3, 73230 Kirchheim unter Teck, Germany.

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.
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http://dx.doi.org/10.1038/nrrheum.2017.140DOI Listing
November 2017

Individual values of antineutrophil cytoplasmic antibodies do not correspond between antigen-specific assays.

Clin Chem Lab Med 2018 01;56(2):e39-e42

Department of Laboratory Medicine, University Hospitals Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium, Phone: +32 16 347009, Fax: +32 16 34 79 31.

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http://dx.doi.org/10.1515/cclm-2017-0362DOI Listing
January 2018

Evaluation of automated multi-parametric indirect immunofluorescence assays to detect anti-neutrophil cytoplasmic antibodies (ANCA) in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Autoimmun Rev 2016 Jul 9;15(7):736-41. Epub 2016 Mar 9.

Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Objectives: The aim of this multicenter EUVAS study was to evaluate the diagnostic performance of multi-parametric indirect immunofluorescence (IIF) assays to detect anti-neutrophil cytoplasmic antibodies (ANCA) in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Patients And Methods: The study included 912 samples from diseased controls and 249 diagnostic samples from GPA (n=183) and MPA (n=66) patients. The performance of two automated multi-parametric assays [Aklides (Medipan/Generic Assays) and EuroPattern (Euroimmun)] combining IIF on cellular and purified antigen substrates was compared with two manual IIF analyses and with commercially available ELISAs for MPO- and PR3-ANCA (Euroimmun).

Results: The area under the curve (AUC) of the receiver operating characteristics (ROC) curve to discriminate AAV from controls was 0.925, 0.848, 0.855 and 0.904 for, respectively, the two manual analyses, Aklides and EuroPattern, and 0.959, 0.921 and 0.886 for, respectively, antigen-specific ELISA, antigen-coated beads, and microdot, respectively. Variation in pattern assignment between IIF methods was observed.

Conclusion: The performance of IIF depends on the substrate used and the definition of IIF patterns. The performance of automated IIF is improved by multi-parameter testing (combined IIF and antigen-specific testing). Given the variability between IIF methods, the diagnostic importance of this technique is questioned.
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http://dx.doi.org/10.1016/j.autrev.2016.03.010DOI Listing
July 2016

[Fever, skin changes, myalgia - from early symptom to diagnosis].

Dtsch Med Wochenschr 2015 Sep 11;140(18):1342. Epub 2015 Sep 11.

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http://dx.doi.org/10.1055/s-0041-105988DOI Listing
September 2015

[Fever, skin changes, myalgia--from early symptom to diagnosis].

Dtsch Med Wochenschr 2015 Jul 31;140(15):1137-44. Epub 2015 Jul 31.

Kreiskliniken Esslingen, Akademisches Lehrkrankenhaus der Universität Tübingen.

New clinical symptoms in the context of rheumatic inflammatory system diseases require the exact knowledge of the anamnestic symptom-characteristic. Fever, skin changes and myalgia are frequent and unspecific symptoms that need a particularly broad-based interdisciplinary approach to identify potential causes. The attending physician can thereby avoid unnecessary, expensive and somewhat stressful tests. This article is intended to give important advice for everyday practice in step-wise diagnostics.
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http://dx.doi.org/10.1055/s-0041-103381DOI Listing
July 2015

A vasculitis centre based management strategy leads to improved outcome in eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA): monocentric experiences in 150 patients.

Ann Rheum Dis 2013 Jun 11;72(6):1011-7. Epub 2012 Aug 11.

Department of Rheumatology, University Hospital Schleswig-Holstein and Klinikum Bad Bramstedt, Bad Bramstedt, Germany.

Objective: To evaluate a vasculitis centre based management strategy for eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA).

Methods: A retrospective cohort study at a vasculitis referral centre was performed. All EGPA patients admitted from 1990 to 2009 were included. A structured interdisciplinary work-up for proof of diagnosis, Disease Extent Index and Birmingham Vasculitis Activity Score was performed. Immunosuppressive therapy was initiated and regularly adapted. Treatment targets were induction and maintenance of remission according to definitions given by the European League Against Rheumatism and the European Vasculitis Study Group. Outcomes were mortality, rate of remission, relapses, adverse events and prednisolone-dose.

Results: Out of 269 patients with suspected EGPA 150 fulfilled the inclusion criteria. Of those, 104 had more than one follow-up visit resulting in a mean follow up of 53±4.9 months. By using additional data sources the follow-up concerning survival was extended to 92±5 month. Severe organ manifestations occurred at heart (46%), kidney (18%) and lungs (10%). Cyclophosphamide was used in 107 patients (71%). The prednisolone-doses of all patients were within the targeted range (i.e. ≤7.5 mg) in 69% of the total follow-up time; the median dose at end of follow-up was 5mg/d. The 10-year survival rate was 89% resulting in mortality comparable to the general population (SMR 1.29). Only patients with cardiac failure associated with EGPA had an increased mortality (SMR 3.06).

Conclusions: Regular re-evaluation and target-orientated adaption of therapy may lead to normalization of life expectancy and attenuation of disease progression. Continued centre based interdisciplinary treatment should be standard of care.
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http://dx.doi.org/10.1136/annrheumdis-2012-201531DOI Listing
June 2013

Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps.

Arthritis Rheum 2012 Apr 27;64(4):982-92. Epub 2011 Oct 27.

University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Objective: To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity.

Methods: We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty's syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects.

Results: Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients.

Conclusion: Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.
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http://dx.doi.org/10.1002/art.33432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729190PMC
April 2012
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