The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients.

OBJECTIVES: Giant cell arteritis (GCA) is one of the most common forms of vasculitis. There is an abundance of studies which are conducted in a randomised controlled trial setting but limited with respect to cohort size and follow-up time. GeVas is the first large-scale registry for vasculitides in German-speaking countries that enables to evaluate this rare disease. Herein we focus on the subgroup of GCA patients including follow-up data up to one year. METHODS: GeVas is a prospective, web-based, multicentre registry for the documentation of organ manifestations, outcomes, and therapy regimens in vasculitides. Recruitment started in June 2019. By April 2023, 15 centres were initiated and have started to enrol patients. RESULTS: After 4 years, 195 GCA-patients were included in the registry, of which 64% were female and 36% were male. The average age was 76 years at the time of recruitment (IQR=69-82). Seventy-nine percent were included in the registry because of a newly diagnosed GCA and 21% because of a relapse. At the first assessment most of the patients (89%) described general symptoms. Thirty-one percent stated ocular symptoms. Cranial symptoms were documented in 78% of the cases. All patients were documented with immunosuppressive treatment at start, of whom 95% received prednisolone, 16% cyclophosphamide, 20% methotrexate, and 48% tocilizumab. After three months 62% and after one year 91% of the patients achieved remission. CONCLUSIONS: Regarding demographics, clinical manifestations and diagnostics, our study showed a similar composition compared to other studies. However, our data differed in terms of treatment regimens.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788. FINDINGS: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment. INTERPRETATION: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis. FUNDING: Novartis Pharma.

Immune Checkpoint Inhibitor-Related Adverse Effects and 18F-FDG PET/CT Findings.

Immune checkpoint inhibitor (ICI) treatments activate T cells against tumors. Activated T cells attack not only the tumor but also healthy cells, causing an autoimmune reaction in various tissues. These immune-related adverse effects (IRAEs) cause 18F-FDG uptake in various tissues due to inflammation. It is important to recognize and report these findings on 18F-FDG PET/CT studies. 18F-FDG PET helps to determine the presence, location, and severity of IRAEs. In severe cases, ICI treatments are interrupted or suspended and antiinflammatory treatments are started. 18F-FDG uptake due to IRAEs may mimic metastases or disease progression. Their presence may also help in predicting response to treatment and have prognostic implications. In this review article, we provide basic information about ICI treatments, IRAEs, and 18F-FDG PET/CT findings.

Multiparametric Analysis of Connective Tissue Disease Specific Autoantibodies Using a Spot Immunoassay.

BACKGROUND: Based on advances over several decades, a significant number of autoantibodies are aiding the diagnosis, differential diagnosis and even prognostic estimates of patients with connective tissue diseases (CTD). Based on cost and time constraints, multiplex assays are used more and more in routine practice. Here we describe the evaluation results of a novel spot immunoassay (SeraSpot® ANA) for multiplex analysis of the main CTD specific autoantibodies, which is based on autoantigens immobilized on microtitration plates. METHODS: For evaluation of the ANA spot immunoassay, comprising dsDNA, histone, nucleosome, Scl-70, U1-RNP (mixture of U1-RNP-A, C, and 70k), Sm (SmD), RibP (P0), Ro52/TRIM21, Ro60, La/SS-B, CENP-B, Jo-1, PM/ Scl-100, and Ku as target antigens, sera of 489 patients with systemic autoimmune rheumatic disease (SARD), sera of 54 patients with herpes virus infections, and sera of 202 apparently healthy individuals (AHI) were tested. RESULTS: The concordance between the SeraSpot and EIA results of disease specific autoantibodies (AABs) was high (94 - 97% for CENP-B, Jo-1, Scl-70, Sm, La, Ro52 and Ro60 antibodies) to moderate (86.7% for dsDNA antibodies), and no major differences in the frequency of these AABs in patients with CTD were observed. In SLE patients, the SeraSpot results of dsDNA antibodies correlate better with CLIFT results and HEp-2 cell pattern than the EIA results. The diagnostic specificities of SLE, SSc, SjS, and myositis specific AABs are very high (96.5 - 100%) compared to apparently healthy individuals, but lower with regard to serological differentiation of the SARD entities (86.6 - 99.1%). However, very high positive likelihood ratios (10 up to infinite) could be obtained by disease specific AAB profiles. CONCLUSIONS: The SeraSpot® ANA assay allows the detection of 14 AAB specificities used for the diagnosis and dif-ferentiation of CTD in one approach. Although the concordance between the SeraSpot® assay and EIA is moderate for most of the tested AAB specificities, defined AAB profiles are suitable for the correct diagnosis of the CTD entities. If time matters, the authors suggest the parallel employment of immunofluorescence on HEp-2 cells and the SeraSpot® ANA assay for screening and specific AAB determination of patients with suspected CTD.

[Survey of rheumatologists in Saxony, Saxony-Anhalt and Thuringia regarding the occupational situation and activities in further education: no way out of the undersupply of rheumatological care]. / Befragung von Rheumatologen in Sachsen, Sachsen-Anhalt und Thüringen zu Weiterbildungstätigkeit und beruflicher Situation: Kein Ausweg aus der rheumatologischen Unterversorgung.

INTRODUCTION: Many regions in the middle of Germany have a deficit in specialized rheumatological care. A survey was undertaken to investigate whether the regional capacities for rheumatological advanced training are sufficient to provide an adequate number of rheumatologists in the future. METHODS: All 91 rheumatologists registered in Saxony, Saxony-Anhalt and Thuringia received a questionnaire that was sent back by 66% of the recipients (23 responses from Saxony, 19 from Saxony-Anhalt, 18 from Thuringia). Of the rheumatologists 41 were in private practice, 19 worked in an inpatient department and the mean duration of professional activity was 18 years. RESULTS: Over the last decade the number of patients treated by rheumatologists in private practices increased from 1200 to 1500 per quarter year (p < 0.001), whereas the number of first consultations rose from 100 to 130 per quarter year (p = 0.06). The waiting time for a first consultation rose from 8 to 11 weeks (p = 0.01), 32% of the responders indicated that the conditions for outpatient treatment had either improved or had remained constant during the last 10 years, whereas 60% reported a mild or marked deterioration and 48% stated that the number of rheumatologists had decreased within the same time frame. Only 20% indicated that they had a definite successor in the practice after retirement. All inpatient departments also had an outpatient office. During the last 10 years, the number of consultations per quarter year decreased from 1100 to 700 (not significant), while the waiting time doubled from 6 to 12 weeks (rounded mean). Of the rheumatologists in private practice eight are currently entitled to provide advanced education in rheumatology, with a median training period of 18 months; however, none of the responding physicians had actually brought assistant doctors to the final examination during the last decade and only one prospective rheumatologist was currently completing training in a private practice setting. Only 6 out of 12 inpatient rheumatological facilities are entitled to educate rheumatologists over the whole training period, 5 facilities were not involved in training at all and 7 indicated that they lacked applications for rheumatology training. During the last 10 years, 37 rheumatologists completed the training of which 18 went into private practice, 8 worked as general practitioners and 29 remained in the region of their initial training. CONCLUSION: Given the increase in the number of outpatients served, the volume of training activities in rheumatology is hardly sufficient to improve the deficit of rheumatological care in the middle of Germany.

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

Rituximab therapy in patients with refractory dermatomyositis or polymyositis: differential effects in a real-life population.

OBJECTIVES: While a double-blind trial has not met its endpoint, rituximab (RTX) is still seen as useful in refractory DM and PM. In this study we analysed the charts of all patients receiving RTX for myositis in our institutions for objective outcome parameters. METHODS: In a retrospective way, the charts of all patients with PM or DM who received RTX were analysed for glucocorticoid dose, creatine phosphokinase (CPK) and lung function tests, as well as for serious adverse events. RESULTS: A total of 19 patients were identified, 1 of whom died from aspiration pneumonia 3 weeks after the first RTX infusion. The charts of 18 patients (13 PM, 5 DM) could be further analysed. In addition to the fatal pneumonia, six more severe infections were seen. One patient developed hypogammaglobulinaemia. Two patients had mild infusion reactions. Under RTX, both CPK and daily prednisolone dose were reduced by week 18. Six of eight patients with alveolitis improved under RTX. Overall, 9 of 13 PM patients responded. Six of the responders and two patients without documented response, all anti-synthetase syndrome patients, were re-treated. In contrast, all five DM patients responded and none required re-treatment. CONCLUSION: In a real-life population of patients with severe, refractory PM or DM, objective improvement was seen in the majority of patients with regard to CPK and lung function tests, and glucocorticoids could be reduced. In contrast to the subgroup with DM, where one cycle of RTX appeared sufficient, patients with anti-synthetase syndromes commonly experienced flares necessitating RTX re-treatment. Infections are of concern.

Classification of vascular disorders in the skin and selected data on new evaluation and treatment.

Cutaneous vascular disorders are common. They include arteries, veins, and lymphatic vessels, or a mixture of them. In this review, we discuss classification, new developments in understanding and treatment of vascular diseases. We focus on infantile hemangiomas and drug therapy, vasculitides with new vasculitic syndromes, yellow nail syndrome and localized lymphatic malformations. Benign cutaneous vascular lesions may be a sign of severe internal diseases. In many cases multidisciplinary treatment is important. The dermatologist can often act as a pilot for these patients.

Efficacy and safety of rituximab treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitides: results from a German registry (GRAID).

OBJECTIVE: Rituximab (RTX) therapy is a treatment option in patients with refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We investigated the tolerability and clinical efficacy of RTX in a cohort of patients with refractory AAV. METHODS: Clinical and safety data of patients with AAV treated with RTX were retrospectively assessed from the data of a German national registry. RESULTS: In total, 58 patients were included in this analysis (50/58 with granulomatosis with polyangiitis; 8/58 with microscopic polyangiitis who received at least 1 cycle, 17 patients who received 2 cycles, and 3 patients who received 3 cycles of RTX). Response was classified as complete and partial in 22 (40%) and in 29 cases (52.7%), respectively. Four patients (7.3%) were classified as nonresponders. CONCLUSION: RTX was well tolerated with good clinical efficacy in patients with refractory AAV.

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID).

INTRODUCTION: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. METHODS: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. RESULTS: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). CONCLUSIONS: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Psoriatic arthritis.

Psoriatic arthritis (PSA) is an entity of inflammatory joint disease associated with psoriasis. PSA belongs to the heterogeneous group of seronegative spondylarthropathies. Both peripheral joints and axial skeleton can be affected in a characteristic pattern. In addition to that, enthesitis and dactylitis are important extracutaneous manifestations. Uveitis anterior is temporarily seen in about one quarter of PSA patients. There is a closer relationship of nail and joint disease. This review provides data on drug and physical treatment options. In particular DMARDS and inhibitors of tumor necrosis factor alpha are established therapies with importance for quality of life and long term outcome. New drugs are tested in various trials.

Management of osteoporosis-related bone fractures: an integrated concept of care.

INTRODUCTION: Multidisciplinary medical management of osteoporosis and osteoporosis-related fractures is still an important treatment issue today. In view of ethiopathology of osteoporosis and the future demographic development an increasing socioeconomic burden has to be estimated. A prerequisite for an effective secondary prophylaxis of osteoporotic fractures is the implementation of a treatment network, with inclusion of all partners involved in patient's care. Therefore, special attention should be paid to formation and establishment of centres with multidisciplinary and integrated treatment concepts. This paper outlines the concept of a clinical centre for diagnosis and therapy of osteoporosis established 4 years ago. Furthermore, a concept of integrated care of osteoporosis-related fractures is introduced and the obtained data of a 2-year follow-up analysis will be presented. METHODS: The establishment of an osteoporosis centre at a university teaching hospital as well as certification according to the Dachverband Osteologie (DVO) guidelines were necessary. Recruitment of contract partners on both sides, health insurances and outpatient general practitioners as well as specialist doctors, was also essential. The implementation of an osteoporosis coordinator was a step to put the treatment concept into practice. RESULTS AND DISCUSSION: Based on the recommendations of DVO guidelines, all diagnostic and therapeutic requirements of osteoporosis can be met by the team of consultant specialists at a clinical osteoporosis centre. In the described treatment concept of integrated care, 44 patients suffering of osteoporosis with a consecutive fracture could be included. Mean age was 77. Inclusion criteria were spinal fractures (61%), proximal femoral fractures (27%) and peripheral fractures (12%). Fifty percent of patients included into the contract had not received previous osteoporosis medication. Sixty-eight patients who met the inclusion criteria could not be included due to the lack of compliance (42%), patients' disapproval (34%) or incomplete treatment and documentation algorithm (24%). Special attention should focus on the completion of standardised diagnosis and documentation. The high amount of time and personnel required has proven the importance of the introduction of an osteoporosis coordinator to be essential.

Fixed drug eruption followed by lichen aureus during abatacept add-on therapy of rheumatoid arthritis.

BACKGROUND: Abatacept is a soluble fusion protein approved as add-on drug in rheumatoid arthritis. MAIN OBSERVATIONS: Here we report the first case of fixed drug eruption followed by lichen aureus due to abatacept in a 67-year-old woman. CONCLUSION: Fixed drug eruption is an unexpected drug reaction for abatacept, since T-cell activation is inhibited.

Leg ulcers are a diagnostic and therapeutic challenge.

Leg ulcers are common. They cause a substantial burden to the patient and society. However, there is no need for therapeutic nihilism. The target of leg ulcer therapy is the individual patient. To be treated in a rational and successful way, exact diagnosis of the underlying cause(s) and associated diseases is necessary. This can be done in the most effective way with an interdisciplinary approach. The collection of cases demonstrates the need for careful clinical investigation substantiated and supported by vascular, histopathologic, and microbiologic techniques whenever needed. It is difficult to heal every ulcer completely, but improvement of the medical situation as well as the quality of life of the patient is possible in most cases.