Fibroblast Activation Protein Inhibitor-Positron Emission Tomography in Aortitis: Fibroblast pathology in active inflammation and remission.

OBJECTIVES: Epigenetically modified fibroblasts contribute to chronicity in inflammatory diseases. Reasons for the relapsing character of large vessel vasculitis (LVV) remain obscure, including the role of fibroblasts, in part due to limited access to biopsies of involved tissue.68Ga FAPI-46 (FAPI)-PET/CT detects activated fibroblasts in vivo. In this exploratory pilot study, we tested the detection of fibroblast activation in vessel walls using FAPI-PET/CT in LVV with aortitis. METHODS: 8 LVV patients with aortitis and 8 age- and gender-matched controls were included. Distribution of FAPI uptake was evaluated in the aorta and large vessels. FAPI-uptake was compared with MRI inflammatory activity scores. Imaging results were compared with clinical parameters such as serum inflammatory markers, time of remission and medication. RESULTS: Three aortitis patients were clinically active, five in remission. Irrespective of activity, FAPI uptake was significantly enhanced in aortitis compared with controls. Patients in remission had a mean duration of remission of 2.8 years (range 1-4 years), yet significant FAPI uptake in the vessel wall was found.In remitted aortitis, MRI inflammatory scores were close to be negative, while in 4/5 patients visually identifiable FAPI uptake was observed. CONCLUSIONS: This pilot feasibility study shows significant tracer uptake in the aortic walls in LVV. FAPI positivity indicates ongoing fibroblast pathology in clinically remitted LVV.

[Castleman's disease in the rheumatological practice]. / Morbus Castleman in der rheumatologischen Praxis.

The term Castleman's disease encompasses a group of rare lymphoproliferative diseases that show histopathological similarities in lymph node biopsy. Diagnostic criteria and a specific ICD-10 code have been available for a few years. Case studies listed at the beginning illustrate that close cooperation between clinicians and pathologists is required to enable a reliable diagnosis. For an optimal histopathological assessment, the pathologist is also dependent on the removal of a complete lymph node. Before distinguishing a potentially fatal multicentric idiopathic Castleman's disease from the resectable unicentric form, which is important in terms of prognosis and treatment, early diagnosis presupposes that Castleman's disease is considered in the differential diagnosis. Various immune phenomena and overlaps with autoimmune diseases can increase the probability of misdiagnosis or undetected cases in the clinical routine of rheumatologists. The intention of the present overview is therefore to point out the similarities with autoimmune diseases that are relevant for differential diagnoses and to point out situations that justify a review of the previous diagnosis.

[Local and systemic light chain amyloidosis in patients with rheumatic diseases]. / Lokale und systemische Leichtkettenamyloidosen bei Patienten mit rheumatologischen Erkrankungen.

BACKGROUND: In patients with chronic inflammatory rheumatic diseases various types of amyloidosis diseases can occur. If amyloidosis is suspected a differentiation between local and systemic amyloid deposits needs to be made as well as between AL, AA and other forms of amyloidosis. OBJECTIVE: The aim is the characterization of local and systemic AL amyloidosis in rheumatic diseases, demonstration of diagnostic algorithms and prognostic factors as well as a discussion of the treatment options. MATERIAL AND METHODS: The cohort of patients with amyloidosis at the amyloidosis center in Heidelberg is presented and compared to other amyloidosis cohorts as well as a discussion of the treatment options. RESULTS: A monoclonal gammopathy can be observed in many patients with various rheumatic diseases. In patients with Sjogren's syndrome nodular cutaneous deposits of local AL amyloid can be observed; however, the occurrence of systemic AL amyloidosis has so far been reported only in a few isolated cases of patients with rheumatic diseases. CONCLUSION: In patients with rheumatic diseases, the development of a mostly local AL amyloidosis must also be considered in addition to AA amyloidosis. An early diagnosis is crucial to prevent further deterioration of organ function in patients with clinical indications of a systemic amyloidosis. The differentiation between AA and AL amyloidosis is essential in order to initiate a targeted treatment.

[Autologous hematopoietic stem cell transplantation for systemic sclerosis : Position statement of the stem cell therapy working party of the German Society of Rheumatology]. / Autologe hämatopoetische Stammzelltransplantation bei systemischer Sklerose : Positionspapier des Arbeitskreises Stammzelltherapie der Deutschen Gesellschaft für Rheumatologie.

There have been three randomized controlled trials on autologous hematopoietic stem cell transplantation (AHSCT) in systemic sclerosis (SSc) that demonstrated significant superiority with respect to survival, improvement of cutaneous fibrosis, lung function and quality of life compared to standard treatment; however, these advantages must be carefully weighed against the transplantation-related risks. For this reason, an expert group from the stem cell therapy working party of the German Society for Rheumatology (DGRh) has now developed recommendations for the use of AHSCT in SSc. Based on the high-quality evidence, AHSCT is considered as the standard option for the treatment of selected SSc patients. Potential candidates for AHSCT are those with early, rapidly progressive, diffuse cutaneous SSc with visceral manifestations who have not yet developed severe damage to internal organs. A close cooperation between rheumatologists and transplantation centers is crucial for optimizing patient selection and treatment outcomes.

[Autoinflammatory syndromes and AA amyloidosis]. / Autoinflammatorische Syndrome und Amyloid-A-Amyloidose.

Autoinflammatory syndromes (AIS) are characterized by uniform attacks often with febrile episodes, exanthema, abdominal pain, muscle and joint pain. Patients show markedly elevated levels of the inflammatory serum parameters C­reactive protein (CRP) and systemic amyloid A (SAA) during an attack. The origin of the family of the patient and the duration of the attacks are helpful to find the appropriate diagnosis. Molecular genetic tests are used to confirm the clinical diagnosis of an AIS. Colchicine can prevent attacks of familial Mediterranean fever but not the other forms of AIS. In refractory cases anakinra or canakinumab can be used to control the inflammatory exacerbations. Systemic AA amyloidosis can develop secondary to any insufficiently treated chronic inflammatory disease. Renal involvement is the predominant initial organ dysfunction, which can be detected early on by the evaluation of proteinuria. If AA amyloidosis can be diagnosed early and successfully treated, the renal function and the function of other organs can be preserved for many years. In patients with advanced AA amyloidosis renal failure with the subsequent necessity for dialysis can often no longer be prevented. These patients should be treated to prevent involvement of the stomach, intestines and heart.

[Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany]. / Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland.

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.

Large Variability of Frequency and Type of Physical Therapy in Patients in the German Network for Systemic Sclerosis.

OBJECTIVE: To determine the type and frequency of physical therapy (PT) prescribed by physicians for patients in the registry of the German Network for Systemic Sclerosis. METHODS: The data for 4,252 patients were analyzed using descriptive statistics, chi-square tests, and odds ratios (ORs). RESULTS: Overall, 37.4% of patients (1,590 of 4,252) received PT at the end of a yearly follow-up. The most frequently used type of PT was lymphatic drainage (n = 1,061, 36.8%), followed by exercise therapy (n = 1,047, 36.3%) and heat therapy (n = 689, 23.9%). More than three-fourths of treated patients (82%) received 1 or 2 different forms of PT simultaneously. The prescription of PT was associated with the extent of skin fibrosis as measured by the modified Rodnan skin thickness score (<10 [41.8% of patients], 11-20 [55.8% of patients], and >21 [63.9% of patients]; P < 0.001). Patients with musculoskeletal involvement (e.g., arthritis, muscle weakness, joint contractures, tendon friction rubs) had a higher chance of receiving PT than patients without these symptoms, with corresponding ORs ranging from 1.96 (95% confidence interval [95% CI] 1.69-2.28) for joint contractures to 3.83 (95% CI 2.89-5.08) for arthritis. When comparing the type of PT prescription across the initial and all follow-up visits from 2003 to 2017, significant alterations with a decreasing frequency of patients receiving PT could be observed (P = 0.001). CONCLUSION: To our knowledge, this is the first study reporting the use of PT in patients with systemic sclerosis (SSc) in a large cohort. Although SSc is characterized by considerable disability and restriction of motion, <40% of patients received PT.

[Evidence-based treatment recommendations for familial Mediterranean fever : A joint statement by the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Evidenzbasierte Therapieempfehlungen für das familiäre Mittelmeerfieber : Eine gemeinsame Stellungnahme der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) in Germany is a rare, genetically linked disease of childhood and adolescence, which is characterized by recurrent febrile episodes and clinical signs of peritonitis, pleuritis and arthritis. Treatment with colchicine is effective and well-tolerated in the majority of patients; however, some patients do not sufficiently respond to this treatment or are intolerant to colchicine. For these patients first-line treatment with biologics which block interleukin-1 can be used. OBJECTIVE: The aim was to formulate evidence-based treatment recommendations for patients with an insufficient response and intolerance to colchicine treatment. METHODS: Based on a literature search and the European League Against Rheumatism (EULAR) recommendations on FMF from 2016 the appointed members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) convened to work out and form a consensus in a joint statement on evidence-based treatment recommendations on FMF. RESULTS: After intensive discussions all decisions were in concordance. A total of 5 superordinate principles and 10 recommendations were agreed upon. DISCUSSION: The joint activities of the GKJR and the DGRh were successfully concluded in a timely manner. The recommendations form a good basis for optimal treatment of all age groups of patients with FMF.

Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes.

OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.

Absence of cardiotoxicity with prolonged treatment and large accumulating doses of pegylated liposomal doxorubicin.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is used as a second-line therapy for gynecologic cancers, with a better short-term toxicity profile compared to doxorubicin or other anthracyclines. METHODS: We screened 14 patients with recurrent gynecologic cancers, who underwent prolonged treatment with large cumulative doses of PLD for overt or subtle signs of cardiotoxicity (CTX) using standard and advanced echocardiography techniques [3D volumetric method for left ventricular ejection fraction (LVEF) and left ventricular/right ventricular global longitudinal strain]. Half the patients had previous echocardiographic studies available for comparison. RESULTS: The average PLD treatment duration was 23.6 ± 10.8 months (range 13-57), accumulating dose of 1387 ± 483 mg (range 780-2538 mg). The study group had a normal LVEF both by 2D-echo (60 ± 5%, range 50-67) and 3D echo (58 ± 5%, range 46-63). Two patients (14%) were found to have minimally reduced ejection fraction by 2D and 3D echo (50%/46% and 51%/49%, respectively) that did not meet the current definition of CTX. For the seven patients who had consecutive echocardiography studies, the average LVEF remained stable between studies (59 ± 7, 60 ± 9 and 58 ± 10.5% for the latest study, previous, p < 0.79, and most remote study p < 0.9); No change was found in average left ventricular/right ventricular global longitudinal strain as well: -20.8 ± 4.6% at the latest study and -19.3 ± 2.6% for the previous (p < 0.51). CONCLUSION: No prevalent or incident cases of cardiotoxicity were found despite prolonged treatment with large cumulative doses of PLD, adding to previous reports on shorter treatment duration.

Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.

OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1ß (IL-1ß) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants. METHODS: A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1ß release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. RESULTS: The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. CONCLUSION: Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1ß and non-IL-1ß-mediated inflammatory pathway activation.

[Cryoglobulinemic vasculitis]. / Kryoglobulinämische Vaskulitiden.

Cryoglobulinemic vasculitis is a disease of the small arteries and affects the skin, joints, peripheral nerves, kidneys and other organs. Even small amounts of cryoglobulins can lead to severe impairment for the patient but the detection of such low amounts of cryoglobulins can be difficult. The causes of cryoglobulinemic vasculitis include monoclonal hematological diseases, autoimmune diseases and chronic infections. Therapy involves treatment of the underlying disease and glucocorticoids, rituximab and plasmapheresis depending on the severity of the vasculitis. Recognition of typical clinical symptoms is essential in order to initiate appropriate laboratory diagnostic procedures. Sometimes many investigations are necessary. In the absence of clinical trials treatment recommendations can often only be derived from registry data.

[Causes and treatment of systemic amyloidosis]. / Ursachen und Therapie der systemischen AA-Amyloidose.

BACKGROUND: Systemic amyloidoses are rare protein deposition disorders, which are often diagnosed in an advanced stage of the disease due to non-specific symptoms. Any chronic inflammatory disease can lead to an AA-type amyloidosis. AIM: This paper summarizes the current state of the art of diagnosis and treatment of AA amyloidosis and presents data from the past 10 years of our amyloidosis center. MATERIAL AND METHODS: Our data represents an analysis of our cohort of patients with amyloidosis and a selective research in the PubMed database for AA amyloidosis. RESULTS: The underlying diseases comprise autoinflammatory syndromes, polyarthritis, and chronic inflammatory bowel and lung diseases. Renal organ involvement is the most prevalent in AA amyloidosis. It can be detected early through the evaluation of proteinuria. The treatment depends on the individual underlying disease. Patients without an associated inflammatory disease are considered to have idiopathic AA amyloidosis and empiric treatment is mandatory. DISCUSSION: Survival of this fatal disease has recently improved due to the new diagnostic tools and treatment options; however, early diagnosis plays a crucial role in the prevention of end-stage renal failure. New therapeutic strategies aim to remove existing amyloid deposits.

[Treatment and course of a man with systemic sclerosis before and after hematopoetic blood stem cell transplantation]. / Therapie und Verlauf bei einem Patienten mit systemischer Sklerose vor und nach Blutstammzelltransplantation.

HISTORY AND ADMISSION FINDINGS: A 66-year-old patient presented in our clinic with increasing painful swelling of his hands, whole body stiffness, weight loss and dyspnoea upon exercise. EXAMINATIONS: The physical examination revealed a marked skin sclerosis of hands, extremities and the face. Fist closure was impossible. Pulmonary CT scan showed lung fibrosis and ground glass opacities. Antinuclear antibodies and antibodies against Scl70 were positive. CRP, LDH, NT-Pro-BNP were elevated. DIAGNOSIS, TREATMENT AND COURSE: A diffuse cutaneous systemic sclerosis with an active interstitial pneumonia and lung fibrosis was diagnosed. Three pulses of cyclophosphamide 1.4 g every three weeks were ineffective to halt the progression of skin sclerosis, joint contractures and decline of pulmonary function. Mobilisation chemotherapy was initialized and blood stem cells were harvested. Blood stem cells were reinfused after myeloablative chemotherapy with melphalan. A maintainance therapy with mycophenolic acid was initiated after recovery of hematopoiesis. Six months after blood stem cell transplantation a decrease of skin sclerosis and an increasing recovery of joint mobility and physical strength was observed. CONCLUSION: Patients with a progressive systemic sclerosis and further risk factors should be treated with high-dose chemotherapy with blood stem cell transplantation before organ function is severely compromised. In cases with contraindications against cyclophosphamide or anti-thymocyte-globulin melphalan can be discussed as an alternative.

[Chronic inflammation and AA amyloidosis]. / Chronische Entzündung und AA-Amyloidose.

Systemic AA amyloidosis is a severe complication of chronic inflammatory diseases. Renal involvement is the predominant organ manifestation. Patients who are at risk for developing AA amyloidosis should be screened for microalbuminuria. The goal of therapy is an effective control of the acute phase reaction. A well controlled blood pressure and nephroprotective treatment contribute to the maintenance of renal function. In case of progressive amyloidosis dialysis is required. Renal transplantation can be performed if the underlying disease is well controlled.

Familial Mediterranean fever in Germany: clinical presentation and amyloidosis risk.

OBJECTIVE: To characterize patients with familial Mediterranean fever (FMF) with and without AA amyloidosis living in Germany. METHOD: Clinical and genetic data from 64 FMF patients were analysed for amyloidosis risk factors. RESULTS: Fifty-five patients (85%) were of Turkish or Armenian origin. Thirty-one patients (48%) developed FMF symptoms before the age of 16 years. Sixteen patients (26%) became symptomatic after age 20. Symptoms reported were peritonitis (95%), fever (78%), pleuritis (59%), arthralgia (60%), arthritis (32%), erysipelas-like erythema (23%), and vasculitis (8%). FMF diagnosis was delayed for a median of 8.0 years. Genetic analysis confirmed M694V as the most prevalent Mediterranean fever (MEFV) gene mutation in 46 out of 59 patients (78%). M694V homozygosity was associated with an earlier FMF onset (median age 5.5 years, p = 0.0001) and a higher prevalence of peritonitis (p = 0.007) and pleuritis (p = 0.0007) compared to patients without an M694V mutation. AA amyloidosis was detected in 16 patients (25%) at a median age of 36.5 years and tended to be associated with a higher age at disease onset (p = 0.062) and a higher FMF activity score (p = 0.093). AA amyloidosis was significantly associated with a higher age at FMF diagnosis (p = 0.0022). CONCLUSIONS: Clinical symptoms of FMF-affected migrants living in Germany resemble those observed in their home country. In particular, patients with an onset of FMF symptoms after age 20 and a later FMF diagnosis have a high risk of AA amyloidosis. Symptomatic patients who originate from countries with a higher FMF prevalence should be screened for FMF and proteinuria.

[Rheumatic diseases with primary onset in young adults: spondyloarthritis and connective tissue diseases]. / Rheumatische Erkrankungen mit typischer Erstmanifestation im jungen Erwachsenenalter: Spondyloarthritiden und Kollagenosen.

Inflammatory rheumatic diseases can occur at any age. In young adulthood spondyloarthritis and systemic lupus erythematosus in particular present the first symptoms. General practitioners and internists are the first to be contacted by patients. They should be familiar with inflammatory back pain, HLA B27, inflammatory signs in the sacroiliac joints on imaging and extra-articular manifestations in order to transfer patients suspected of having spondyloarthritis to a rheumatologist. The same applies to skin and organ involvement, especially lupus nephritis, in patients with suspected systemic lupus erythematosus, as well as antibody screening in particular for antinuclear antibodies and anti-double stranded DNA (dsDNA) antibodies. Patients are often at the beginning of their professional and family career, therefore, early diagnosis is necessary to initiate an adequate therapy and prevent or minimize long-term damage.