[Treatment of giant cell arteritis: what is in the pipeline?] / Therapie der Riesenzellarteriitis: Was ist in der Pipeline?

Glucocorticoids (GC) represent the standard treatment in remission induction and maintenance in the treatment of giant cell arteritis (GCA). Additive immunosuppressants are currently only recommended in special situations, such as refractory or relapsing disease or in cases of glucocorticoid-induced side effects. Methotrexate has been the standard steroid-sparing agent for many years. Meanwhile, tocilizumab is the first choice for steroid reduction, which was the first biological to be licensed for the treatment of GCA; however, long-term data over more than 3 years are lacking. A number of promising bDMARD and tsDMARD are currently being investigated in randomized controlled trials (RCT), which could contribute to additional effective steroid-sparing options in the treatment of GCA and help to establish an additive GC-sparing medication as the standard treatment in the future. This article gives an overview on current treatment studies for GCA.

[Current guidance of the German Society of Rheumatology for the care of patients with rheumatic diseases during the SARS-CoV-2/Covid 19 pandemic]. / Aktuelle Handlungsempfehlungen der Deutschen Gesellschaft für Rheumatologie für die Betreuung von Patienten mit rheumatischen Erkrankungen während der SARS-CoV­2/Covid 19-Pandemie.

In the current SARS-CoV-2 pandemic there are many questions regarding the safe treatment of patients with inflammatory rheumatic diseases. Many of these questions cannot yet be answered on an evidence-based basis and this does not make patient care easy. The German Society for Rheumatology (DGRh) hopes that these initial recommendations will provide support for specific issues in the care of patients with inflammatory rheumatic diseases in view of the current threat posed by SARS-CoV-2. In order to take advantage of the dynamic worldwide gain in knowledge for our patients, the recommendations will be updated regularly. The updated versions of the recommendations are deposited on the homepage of the DGRh.

[Current treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)]. / Aktuelle Therapie der eosinophilen Granulomatose mit Polyangiitis (Churg-Strauss-Syndrom).

For the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) much less data are available when compared to the other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). At the same time EGPA also differs in many aspects from AAVs. Treatment is guided by the German and international guidelines. An adapted induction therapy is chosen depending on the disease activity, manifestations and factors determining the prognosis. For patients without negative prognostic factors glucocorticoids alone may be sufficient. A medium potent immunosuppressive agent may be added in order to economize on steroids. For patients with severe organ manifestations and adverse prognostic factors, a highly potent immunosuppression usually with cyclophosphamide, is necessary. In cases of remission a maintenance therapy is recommended in the same way as for other AAVs. Recently, a biological, the IL-5 antibody mepolizumab has also become available, although its precise role still has to be established.

[Collagenosis and vasculitis-what is allowed in treatment?] / Kollagenosen und Vaskulitiden ­ Was ist erlaubt in der Therapie?

There has been a substantial improvement in treatment options for rheumatic diseases due to the approval of many new drugs. This general trend is also observable in rare diseases, which are predominant in the field of vasculitis and collagenosis, albeit in a lesser form; however, the usually high costs of new drugs lead to increased scrutiny of prescriptions by health insurances. Many of the medications used do not have an official approval for these indications, so that use outside the approval, a so-called off-label use, must often be strived for. Whereas this often does not occur with conventional immunosuppressive drugs due to the comparatively low risk of recourse, in many situations cost coverage for an off-label use should be requested in advance for biologicals.

[Clinical spectrum of IgG4-related diseases and the connection to rheumatology]. / Klinisches Spektrum der IgG-4-assoziierten Erkrankungen und der Bezug zur Rheumatologie.

Rheumatologist should be familiar with the concept of IgG4-related disease (IgG4-RD). Due to the clinical spectrum IgG4-RD can fall directly within the scope of rheumatology and are often diagnosed primarily by rheumatologists. Furthermore, IgG4RD are relevant differential diagnoses for many other rheumatic conditions. Finally, there are an increasing amount of data suggesting an important role of immunological processes observed in IgG4-RD for other rheumatic diseases.

Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Diagnostic Value of Procalcitonin in ANCA-Associated Vasculitis (AAV) to Differentiate Between Disease Activity, Infection and Drug Hypersensitivity.

OBJECTIVE: Procalcitonin (PCT) is considered to be a specific marker for severe bacterial infections and sepsis. Elevated PCT levels have been reported in active autoimmune diseases without infection. The aim of this study was to assess the diagnostic value of PCT serum levels in ANCA-associated vasculitis (AAV) patients with respect to infection, disease activity and drug fever using a high sensitive PCT detection method. METHODS: In 53 AAV patients with elevated C-reactive protein (CRP) PCT was determined by the Thermo Scientific BRAHMS PCT sensitive KRYPTOR assay. Patients underwent standardized diagnostic procedures for evaluation of disease activity and infection. RESULTS: 53 patients with AAV and elevated CRP (7.7±6.9 mg/dl, PCT 0.34±1.02 ng/ml) were assessed, 10 had infection with elevated CRP levels of 11.2±10.2 mg/dl and PCT levels of 1.06±2.07 ng/dl. 43 patients had no evidence of infection, 36 of them were presented with AAV with normal or only slightly positive PCT levels in active disease (n=36) (PCT 0.06±0.06 ng/ml). 7 patients had increased PCT levels due to azathioprine hypersensitivity (0.76±1.01 ng/ml). For discrimination between infection and vasculitis activity PCT was more useful than CRP with the best cut-off at 0.1 ng/ml (sensitivity 60%, specificity 92%). CONCLUSION: In contrast to previous studies using semiquantitative PCT assays, the KRYPTOR performs better with respect to discrimination of infection from active AAV. In all patients assessed with active AAV (and without infection) PCT levels remained below the PCT reference limit (0.5 ng/ml) for infections. Drug hypersensitivity seems to be an important differential diagnosis in the setting of elevated CRP and PCT in patients who receive azathioprine.

[Polyarteritis nodosa: differential diagnostics and therapy]. / Polyarteriitis nodosa: Differenzialdiagnostik und Therapie.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium size arteries that may affect various organs. The clinical appearance is very variable. The most common manifestations are of the skin, the peripheral nervous system presenting as mononeuritis multiplex and the mesenteric and renal blood vessels due to the development of stenoses and small aneurysms. Of the cases one third are estimated to be associated with hepatitis B virus (HBV). The therapy depends on the pathogenesis of the disease: primary PAN is treated with immunosuppressants, whereas patients with HBV-related PAN should receive antiviral therapy and plasmapheresis. Differentiating PAN from other forms of vasculitis can be difficult and requires complex differential diagnostics.

Association of ferritin antibodies with Takayasu arteritis.

Takayasu arteritis (TA) is difficult to diagnose because diagnostic biomarkers have not yet been established. In a previous study, we detected autoantibodies against the human ferritin heavy chain protein (HFC) in the sera of patients with giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR). The aim of this study is to evaluate the frequency of autoantibodies against HFC in TA. We established seven ELISA assays for the detection of autoantibodies against HFC. We used the full-length recombinant HFC expressed in Escherichia coli or one of six different HFC peptides as autoantigens: 1-18Aa (98.8 % purity), 19-45Aa (98.8 % purity), 52-78Aa (98.3 % purity), 79-104Aa (98.8 % purity), 105-143Aa (98.4 % purity) and 145-183Aa (98.5 % purity). We collected sera from 48 patients with TA, 36 patients with systemic lupus erythematosus (SLE), 35 patients with arteriosclerosis, 133 patients with febrile diseases, which are known to generate unspecific autoantibodies, and 50 blood donors, which served as controls. The best results were obtained using the ferritin peptides as antigens. By combining the results from the different ELISAs that detect autoantibodies against the HFC peptides 19-44A, 79-104A and 105-144A, we were able to detect ferritin peptide antibodies in 30/48 (62 %) of the TA patients. The frequency was lower than in early GCA and PMR (previous study showed up to 92 %). Positive results were observed in 0/50 (0 %) of the control blood donors, 10/36 (28 %) of the SLE patients, 4/35 (11 %) of the arteriosclerosis patients and 27/133 (20 %) of the fever patients. Considering the lack of biomarkers for TA, autoantibodies against HFC peptides could act as useful markers for TA.

Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

[Atrial myxoma with clinical signs of systemic inflammatory disease]. / Vorhofmyxom mit klinischem Bild einer entzündlichen Systemerkrankung.

Atrial myxomas are detectable in 0.3 % of all autopsies and women are affected three times more often than men. The overall incidence of myxoma is relatively rare with 0.5 per one million inhabitants per year. Clinical signs, such as palpitations, dyspnea, dizziness and syncope or thromboembolic events may be found. Microembolic infarction or a higher expression of interleukin 6 may lead to misdiagnosis, such as vasculitis. This article presents the case of a 25-year-old woman with arthralgia, dysesthesia, staggering vertigo, cutaneous nodules and disturbed vision. Diagnostic procedures did not reveal a reason for these complaints. A therapeutic test with prednisolone did not improve the symptoms. Finally echocardiography showed a large space-occupying lesion in the left atrium which oscillated into the left ventricle during diastole. The patient was transferred to the department of cardiac surgery where the atrial myxoma could be removed without any complications and the patient ultimately made a complete recovery.

Genetics of toll like receptor 9 in ANCA associated vasculitides.

OBJECTIVES: To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV). METHODS: Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly. RESULTS: A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2. CONCLUSIONS: We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.

[Chronic periaortitis]. / Chronische Periaortitis.

Chronic periaortitis is an inflammatory and fibrosing disease presenting as periaortal fibrosis and formation of aortic aneurysms which are mostly localized in the retroperitoneum and occasionally in the mediastinum. Inflammatory vasculitic involvement of large vessels is also possible. In addition to symptoms of systemic inflammation, mechanical complications also occur whereby obstruction of the ureter is the most frequent. The diagnosis is made by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and if the findings are atypical the diagnosis should be confirmed by biopsy. After exclusion of a secondary genesis, in which case therapy of the underlying illness would be necessary, idiopathic chronic periaortitis can be treated with steroids. In cases of refractory and relapsing courses the administration of further immunosuppressive medication can be necessary. Duration of therapy, dosage and indications for immunosuppressive medication are currently unclear and have to be defined in further randomized controlled trials with larger cohorts. If complications occur, interventional or operative treatment can be necessary; in cases of hydronephrosis the placement of double-J-stents is usually sufficient.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.