[The most frequent febrile syndromes and autoinflammatory diseases in adulthood]. / Die häufigsten Fiebersyndrome und autoinflammatorischen Erkrankungen im Erwachsenenalter.

Autoinflammatory diseases are characterized by inflammatory manifestations in various organ systems, whereby recurrent febrile episodes, musculoskeletal complaints, gastrointestinal and cutaneous symptoms frequently occur accompanied by serological signs of inflammation. Autoinflammatory diseases include rare monogenic entities and multifactorial or polygenic diseases, which can manifest as a variety of symptoms in the course of time. Examples of monogenic autoinflammatory diseases are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory and somatic) syndrome. For non-monogenically determined autoinflammatory diseases, the most important representatives in adulthood are adult-onset Still's disease (AOSD) and the Schnitzler syndrome, in which a polygenic susceptibility and epigenetic factors are more likely to play a role.

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.

[Fever in rheumatological diseases]. / Fieber bei rheumatologischen Erkrankungen.

Fever is a frequent and important symptom in patients with rheumatological diseases and can be an expression of activity of the underlying rheumatological disease. There is great variability in the incidence of fever as a symptom of the disease between individual diseases. The growing understanding of the molecular signatures of the diseases can help to explain these discrepancies: A genetic overactivation of potently pyrogenic cytokines is the reason why fever is nearly always present in autoinflammatory syndromes. In contrast, fever is less common in polyarthritis and myositis and mostly limited to severe courses of disease. In the diagnostic work-up of fever, frequent differential diagnoses, such as infections, malignancies, side effects of drugs and hypersensitivity reactions should be considered. This article provides an overview of the physiology of the development of fever, describes the relevance of fever in individual rheumatological diseases and proposes a workflow for the clinical clarification of rheumatological patients who present with fever.

[Hemophagocytic lymphohistiocytosis and macrophage activation syndrome : A multidisciplinary challenge]. / Hämophagozytische Lymphohistiozytose und Makrophagenaktivierungssyndrom : Eine multidisziplinäre Herausforderung.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is characterized by hyperferritinemia, cytopenia, disseminated intravascular coagulopathy and functional disorders of the liver and the central nervous system. The term macrophage activation syndrome is predominantly used for secondary HLH in the context of autoimmune diseases (e.g., systemic juvenile idiopathic arthritis). In addition, malignancies and genetic inborn errors of immunity can predispose to the development of HLH. Infections (e.g., Epstein-Barr virus) in turn represent possible triggers of an acute episode. Due to the unspecific manifestation of the disease, a systematic evaluation of the organ systems is recommended in the clinical and laboratory analytical clarification of hyperinflammatory syndromes. In general, the treatment should be carried out by a multidisciplinary team with expertise in rheumatology, hematological oncology, infectious diseases and intensive care medicine. The primary treatment of HLH usually consists of glucocorticoids and in cases of a rapid deterioration of the condition anakinra (interleukin 1 block) and intravenous immunoglobulins can be employed. Treatment of the underlying disease should be consequently carried out in parallel, together with antimicrobial treatment.

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.

Daratumumab for autoimmune diseases: a systematic review.

OBJECTIVE: Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases. METHODS: A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome. RESULTS: 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%). CONCLUSION: Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.

[Autoinflammatory syndromes]. / Autoinflammatorische Syndrome.

The concept of autoinflammation includes a heterogeneous group of monogenic and polygenic diseases. These are characterized by excessive activation of the innate immune system without antigen-specific T cells or autoantibodies. The diseases are characterized by periodic episodes of fever and increased inflammation parameters. Monogenic diseases include familial Mediterranean fever (FMF) and the newly described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) syndrome. Heterogeneous diseases include adult-onset Still's disease and Schnitzler syndrome. Treatment is aimed at preventing the excessive inflammatory reaction in order to avoid long-term damage, such as amyloid A (AA) amyloidosis.

VEXAS syndrome: a diagnostic puzzle.

The VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset systemic autoinflammatory condition that is caused by an acquired deficiency of the UBA1 gene in hematopoietic progenitor cells. The clinical spectrum of the VEXAS syndrome currently comprises a broad range of phenotypes such as vasculitis, relapsing polychondritis and Sweet's syndrome. In the past, VEXAS patients have left clinicians puzzled and the true nature of this disease has not been captured until late 2020. This viewpoint describes the relevant clinical features of the VEXAS syndrome and reviews different approaches to establish the diagnosis. Finally, future directions within the field of systemic inflammatory diseases caused by somatic mutations are being discussed.

How to treat VEXAS syndrome: a systematic review on effectiveness and safety of current treatment strategies.

OBJECTIVES: To evaluate the effectiveness and safety of current treatment strategies for the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. METHODS: A protocolized systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed. Three databases were searched for reports on treatment strategies for VEXAS. Data from the included publications was extracted and a narrative synthesis was performed. Treatment response was recorded as complete (CR), partial (PR) or none (NR) depending on changes in clinical symptoms and laboratory parameters. Patient characteristics, safety data and previous treatments were analysed. RESULTS: We identified 36 publications with a total of 116 patients; 113 (98.3%) were male. The identified reports included azacytidine (CR 9/36, 25%; PR 14/36, 38.9%), Janus kinase inhibitors (JAKi) (CR 11/33, 33%; PR 9/33, 27.3%), tocilizumab (CR 3/15, 20%; PR 6/15, 40%), allogeneic stem cell transplantation (CR 6/7, 85.7%; one patient died), anakinra (CR 4/5, 80%; NR 1/5, 20%), canakinumab (CR 1/2, 50%; PR 1/2, 50%) and glucocorticoid monotherapy (CR 1/6, 16.7%; PR 4/6, 66.7%). Individual reports were available for TNF inhibitors, rituximab and MTX. Data on adverse events were available for 67 patients (67/116, 57.8%) and included: pneumonia (12/67, 17.9%), other infections (9/67, 13.4%), venous thromboembolisms (6/67, 8.9%), cytopenias (4/67, 5.9%), and acute (4/67, 5.9%) and chronic graft-vs-host-disease (2/67, 2.9%). CONCLUSION: Current data on VEXAS treatment are limited and inhomogeneous. Treatment decisions should be individualized. For the devolvement of treatment algorithms clinical trials are needed. Adverse events remain a challenge, especially an elevated risk for venous thromboembolism associated to JAKi treatment should be carefully considered.

[Autoinflammatory syndromes]. / Autoinflammatorische Syndrome.

The concept of autoinflammation includes a heterogeneous group of monogenic and polygenic diseases. These are characterized by excessive activation of the innate immune system without antigen-specific T cells or autoantibodies. The diseases are characterized by periodic episodes of fever and increased inflammation parameters. Monogenic diseases include familial Mediterranean fever (FMF) and the newly described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) syndrome. Heterogeneous diseases include adult-onset Still's disease and Schnitzler syndrome. Treatment is aimed at preventing the excessive inflammatory reaction in order to avoid long-term damage, such as amyloid A (AA) amyloidosis.

Successful Rescue Therapy With Daratumumab in Rapidly Progressive Interstitial Lung Disease Caused by MDA5-Positive Dermatomyositis.

Melanoma differentiation-associated gene 5 (MDA5) positive dermatomyositis is a rare systemic autoimmune disease that is associated with life-threatening rapidly progressive interstitial lung disease. We report the case of a 19-year-old male patient with a life-threatening disease course caused by rapidly progressive interstitial lung disease that caused respiratory failure despite intensive immunosuppression with multiple agents (steroids, IV immunoglobulins, tofacitinib, cyclophosphamide, mycophenolate mofetil, ciclosporin and rituximab). Rescue therapy with daratumumab, an anti-CD38-antibody, was initiated. Significant pulmonary improvement was noticed after 4 weekly injections of 1,800 mg. After 6 months of follow up, stable disease remission with significant pulmonary improvement and persistent depletion of CD38+ plasma cells and MDA5-antibody titers were seen. This is the first report of the successful use of daratumumab in dermatomyositis. It highlights the potential of CD38 targeted therapies for severe antibody-mediated autoimmune diseases such as dermatomyositis.

[Cocaine-induced vasculitis and mimics of vasculitis]. / Kokain-induzierte Vaskulitiden und Vaskulitis-Mimics.

Cocaine is a psychotropic tropane alkaloid and stimulant drug. Nasal insufflation of cocaine powder is a common route of administration. In Germany, cocaine is frequently adulterated with levamisole, an anthelminthic drug with immunomodulatory effects. Both substances are linked to various autoimmune conditions. Cocaine-induced midline destructive lesions cause a progressive destruction of osteocartilaginous structures within the upper respiratory tract and can mimic localized granulomatosis with polyangiitis. In addition, systemic vasculitis due to cocaine and levamisole has been reported. Differentiation of these conditions from primary vasculitis can be challenging because antineutrophil cytoplasmic antibodies (ANCA) are commonly detected. Early diagnosis of these conditions is crucial as clinical improvement is closely related to drug cessation.

Tocilizumab for the Treatment of Familial Mediterranean Fever-A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician's global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.

[Sarcoidosis as prime example of a granulomatous disease]. / Sarkoidose als Paradebeispiel einer granulomatösen Erkrankung.

Sarcoidosis is the most frequent immunologically related granulomatous disease and can serve as a model for understanding diseases within this category. The evidence on the diagnostics and treatment is so far limited. It is therefore all the more important that two new and significant guidelines on diagnosis and treatment of sarcoidosis were published during the last 2 years. Additionally, there were more new publications, which were considered for this review article. In this context, this review article provides a current update and overview of sarcoidosis. Pathophysiologically, there is an increasing understanding of the complex processes and interactions involved in the inflammatory processes and granuloma formation. The probability of a diagnosis of sarcoidosis is determined by compatible histology, the exclusion of differential diagnoses and if possible evidence of a multiorgan manifestation. The clinical course is variable and ranges from an asymptomatic manifestation to severe life-threatening organ failure. The most frequently affected organ are the lungs. Pulmonary fibrosis is the most severe form and is also decisive for mortality. An increasing focus is on the extrapulmonary organ manifestations, in particular, cardiac, hepatosplenic, gastrointestinal, renal, ocular and neurological involvement. Treatment, which consists primarily of immunosuppression, should be initiated in cases of organ-threatening or quality of life-impairing activity of the disease. Additional organ-specific management must also be evaluated. In cases of organ failure transplantation should be considered. Due to the limited evidence especially for the treatment of multiorgan sarcoidosis, when possible, patients with this disease should be included in clinical trials.

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review.

Introduction: Autoinflammatory diseases (AID) are rare diseases presenting with episodes of sterile inflammation. These involve multiple organs and can cause both acute organ damage and serious long-term effects, like amyloidosis. Disease-specific anti-inflammatory therapeutic strategies are established for some AID. However, their clinical course frequently includes relapsing, uncontrolled conditions. Therefore, new therapeutic approaches are needed. Janus Kinase inhibitors (JAKi) block key cytokines of AID pathogenesis and can be a potential option. Methods: A systematic review of the literature in accordance with the PRISMA guidelines was conducted. Three databases (MEDLINE, Embase and Cochrane Central Register of Controlled Trials) were searched for publications regarding the use of JAKi for AID. Data from the included publications was extracted and a narrative synthesis was performed. Criteria for defining treatment response were defined and applied. Results: We report data from 38 publications with a total of 101 patients describing the effects of JAKi in AID. Data on Type I Interferonopathies, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Familial Mediterranean Fever (FMF), and Behçet's Syndrome (BS) was identified. From a total of 52 patients with type I interferonopathies, in seven patients (7/52, 13.5%) a complete response was achieved, most (35/52, 67.3%) showed a partial response and a minority (10/52, 19.2%) showed no treatment response. For AOSD, a complete or a partial response was achieved by eleven (11/26, 42.3%) patients each. Two sJIA patients achieved complete response (2/4, 50%) and in two cases (2/4, 50%) a partial response was reported. Half of FMF patients showed a complete response and the other half had a partial one (3/6, 50.0%). Amongst BS patients most achieved a partial response (8/13, 61.5%). Five patients showed no response to therapy (5/13, 38.5%). Overall, the most frequent AEs were upper respiratory tract infections (17), pneumonia (10), BK virus viremia (10) and viruria (4), herpes zoster infection (5), viral gastroenteritis (2) and other infections (4). Conclusion: The results from this systematic review show that JAKi can be beneficial in certain AID. The risk of AEs, especially viral infections, should be considered. To accurately assess the risk benefit ratio of JAKi for AID, clinical trials should be conducted.

[Immunoglobulin-G4-related disease]. / Immunglobulin-G4-assoziierte Erkrankung.

After years of confusion about apparently distinct clinical disease symptoms, the term IgG4-related disease (IgG4-RD) has been coined in 2001, uniting these fibroinflammatory clinical entities with a tendency for tumorous enlargement and tissue fibrosis. Over the past two decades, experimental and clinical studies could make astounding progress in the understanding of this elusive disease. By now, we have a reasonable idea of the pathophysiological mechanisms, which opens up new avenues for therapeutic approaches. It seems like a dense lymphoplasmacytic cell infiltrate, consisting of B­cells, IgG4+ plasma cells, follicular T­helper cells, CD4+ cytotoxic T­cells and M2 macrophages induces a smoldering inflammatory reaction with a fibrogenic cytokine milieu. This stimulates fibroblasts to secrete extracellular matrix components, leading to the histopathologically characteristic storiform fibrosis and obliterative phlebitis. Macroscopically, this reaction results in diffuse organ swelling and tumorous lesions. The macroscopic and histological differentiation from conditions mimicking IgG4-RD can be challenging. This is especially true for granulomatous diseases, such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The situation is further complicated by the fact that ANCAs can be positive in IgG4-RD and, vice versa IgG4 antibodies can be elevated in numerous differential diagnoses, such as infections, AAV, sarcoidosis, and malignancies. This article provides an overview of the multifaceted clinical condition of IgG4-RD with respect to the pathophysiology, diagnostic steps and treatment. Furthermore, an overview of the differential diagnoses is discussed especially with respect to granulomatous diseases.

[Differential diagnosis of a vasculitic syndrome of the lower limb]. / Differenzialdiagnose eines vaskulitischen Syndroms der unteren Extremität.

Vasculitides can present with various clinical signs and symptoms. Besides disease-specific organ manifestations, the skin, peripheral nerves and musculature are frequently involved. The combination of elevated serological inflammatory markers, vasculitic skin lesions, active polyneuropathy and immobilizing myalgia of the lower limb musculature is highly suspicious for muscular polyarteritis nodosa (mPAN). Based on the case of a 63-year-old female patient with a vasculitic syndrome confined to the lower limb due to mPAN, important differential diagnoses of the these disease manifestations are discussed. Magnetic resonance imaging of the affected muscles and subsequent muscle biopsy (including skin and fascia) provide the relevant diagnostic data.

[Autoinflammation-differences between children and adults]. / Autoinflammation ­ Unterschiede bei Kindern und Erwachsenen.

Autoinflammatory diseases present as multisystemic inflammation and often manifest in early childhood. In contrast, in a few diseases, e.g., the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) syndrome, the first symptoms occur exclusively in adulthood. This article describes how the phenotypic expression and severity of individual autoinflammatory diseases differ depending on age. Furthermore, differences in the development of organ damage in children and adults are pointed out. In addition to the hereditary periodic fever syndromes, the clinical picture of deficiency of adenosine deaminase 2, the interferonopathies, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome as well as VEXAS and Schnitzler syndromes are highlighted.