[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.

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.

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.

[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.

[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.

[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.

[Visceral leishmaniasis mimicking Felty's syndrome in rheumatoid arthritis treated with methotrexate and etanercept]. / Imitation eines Felty-Syndroms durch eine viszerale Leishmaniasis bei rheumatoider Arthritis unter Therapie mit Methotrexat und Etanercept.

Visceral leishmaniasis (VL) is a chronic parasitic disease caused by pathogens of the genus Leishmania, which can mimic numerous diseases. The leading symptoms of VL (splenomegaly, pancytopenia, fever) can be misinterpreted, especially if autoantibodies are detected, and lead to the misdiagnosis of an underlying rheumatic disease (e.g. systemic lupus erythematosus, Felty's syndrome). Proinflammatory cytokines such as tumour necrosis factor alpha (TNF-α) play an important role in infection control. In this context, there are increasing reports of VL as an opportunistic infection during treatment with anti-TNF­α agents. A case of VL mimicking Felty's syndrome in a patient with rheumatoid arthritis treated with methotrexate and etanercept is presented.

COVID-19 pandemic impairs medical care of vasculitis patients in Germany: Results of a national patient survey.

Objective: To analyze the impact of the COVID-19 pandemic on medical care and vaccination acceptance of vasculitis patients in Germany. Methods: A web-based national survey was developed by rheumatology centers and vasculitis patient advocacy groups. The survey was distributed nationwide by mail and flyers and could be accessed via a QR-code or weblink from December 2021 to April 2022. Descriptive statistics [mean, median, standard derivation (SD), 25%, 75% quantile] were calculated. 95% confidence intervals were presented for responses that were directly related to the impact of COVID-19 on parameters associated with vasculitis patient care. Results: The online survey was completed by 117 patients with small and large vessel vasculitis [granulomatosis with polyangiitis (n = 69), eosinophilic granulomatosis with polyangiitis (n = 16), microscopic polyangiitis (n = 12), giant cell arteritis (n = 17) and Takayasu's arteritis (n = 3)]. Prescheduled rheumatological appointments had been canceled due to the COVID-19 pandemic in 12.6% of the respondents [95% confidence interval (CI), 7.3-20.0%); in 9% (95% CI, 4.5-15.6%)] appointments had been replaced by digital services. Therapeutic regimens were changed (shifted, reduced, or discontinued) due to the pandemic in 15.5% (95% CI 9.5-22.2%). Vaccination coverages were generally high compared to patients with other rheumatic diseases and the general population. Highest vaccination coverage was observed against COVID-19 (98.1% 95% CI 93.9-99.6%). Conclusion: Vasculitis patients experienced changes in medical care during COVID-19 pandemic such as cancelation of prescheduled rheumatology appointments and modifications in therapeutic regimens. The overall acceptance rate for vaccination was comparatively high, particularly for vaccination against COVID-19.

Tocilizumab treatment in refractory polyarteritis nodosa: a case report and review of the literature.

Polyarteritis nodosa (PAN) is a rare systemic vasculitis affecting multiple organs. Current standard treatment includes the use of glucocorticoids and cyclophosphamide. Unfortunately, some patients do not respond to this treatment and other therapeutic options are needed. We present a case of a young male with refractory PAN and ongoing biopsy evidence of active vasculitis despite optimal standard therapies, who was successfully treated with interleukin-6 antagonist, tocilizumab. A 24-year-old male presented with severe immobilizing polyneuropathy and myalgias. Clinical features included fasciitis, tenosynovitis, early signs of polyneuropathy, and panniculitis, which were largely refractory to the standard therapies. The previous unsuccessful treatments included high-dose glucocorticoids, methotrexate, cyclophosphamide, rituximab, anakinra, and intravenous immunoglobulins. Magnetic resonance imaging showed signs of myositis, with muscle biopsy confirming the diagnosis of PAN. Rapid clinical improvement and sustained remission occurred after interleukin-6 inhibition with tocilizumab at increased dose of 800 mg every 4 weeks. The used search strategy identified 20 publications of which four articles were included for the further analysis. In total, we report the clinical outcome of five PAN cases from the literature and the present one. The present case and the systematic review of literature suggest that tocilizumab is a possible treatment option for, otherwise, refractory hepatitis B virus negative PAN. Randomized-controlled trials are required to evaluate the safety and efficacy of tocilizumab in PAN.