[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.

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.

[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.

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.

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.

[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.

[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.

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.

[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.

[Hypereosinophilic syndrome]. / Hypereosinophile Syndrome.

Hypereosinophilic syndrome is a heterogeneous group of diseases characterized by blood hypereosinophilia and eosinophil-related organ damage. A comprehensive diagnostic work-up is necessary to identify underlying conditions and to detect organ involvement, which are important for prognosis. Involvement of the heart is related with a poorer outcome. Some underlying conditions can be treated with targeted therapies, e.g., tyrosine kinase inhibitors. However, glucocorticoids in combination with steroid-sparing drugs are generally used for treatment. Furthermore, the growing understanding of the molecular pathogenesis will lead to new therapies, e.g., the use of anti-cytokine antibodies.

Association of ferritin autoantibodies with giant cell arteritis/polymyalgia rheumatica.

OBJECTIVES: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are relatively common inflammatory disorders. Establishing the diagnosis however may be difficult, since so far no specific biomarkers of the disorders are available. METHODS: As a screening procedure, the authors used protein arrays for the detection of new autoantigens in GCA and PMR. The results of the protein array were confirmed by different ELISAs detecting IgG antibodies against the human ferritin heavy chain, N-terminal 27 amino acids of the human ferritin heavy chain or the homologous peptide of Staphylococcus epidermidis. Sera of patients with only GCA (n=64), only PMR (n=47) and both PMR and GCA (n=31) were used. RESULTS: In the ELISA using the human ferritin peptide, the sensitivity of IgG antibodies against ferritin was 92% in 36 GCA and/or PMR patients before initiation of treatment, 22/32 (69%) in patients with disease flares and 64/117 (55%) in the total cohort including treated and inactive patients. In controls, the false positive rate was 11/38 (29%) in systemic lupus erythematosus, 1/36 (3%) in rheumatoid arthritis, 0/31 (0%) in late onset rheumatoid arthritis, 3/46 (6.5%) in B-non-Hodgkin's lymphoma and 1/100 (1%) in blood donors. In the ELISA using the ferritin peptide of S epidermidis, 89% of 27 patients with untreated GCA and PMR were positive. CONCLUSION: Antibodies against the ferritin peptide were present in up to 92% of untreated, active GCA and PMR patients. They can be useful as a diagnostic marker of PMR and GCA.

[Update Churg-Strauss syndrome]. / Update Churg-Strauss-Syndrom.

The Churg-Strauss syndrome (CSS) is the rarest subtype of the so-called anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and has the lowest frequency of ANCA-positivity (around 30%). In addition to asthma and blood eosinophilia, CSS is characterized by end-organ damage, which can be caused by either vasculitis and/or tissue infiltration of eosinophilic granulocytes. The CSS shares many etiological and clinical features of other hypereosinophilic syndromes. Recently, a distinct genetic background could be demonstrated for both the ANCA-positive and ANCA-negative subtypes of CSS as compared to the other two forms of AAV. Among other cytokines, interleukin-5 (IL-5) could be identified as a key mediator of eosinophilia. Therefore, recent clinical trials in CSS aimed to target IL-5. Outside of clinical trials, treatment of CSS is adapted to disease stage and activity, as recommended for other types of AAV.

[Esophagitis during immunosuppression]. / Ösophagitis unter Immunsuppression.

Esophagitis due to cytomegalovirus (CMV) has mostly been described in patients with acquired immunodeficiency syndrome (AIDS). Distal and hemorrhagic ulcerations are characteristic. A CMA esophagitis can, however, also occur in patients with no human immunodeficiency virus (HIV) infection as a complication of immunosuppressive therapy. In the case example presented here the disease was due to an excessive dosage of prednisolone medication over a period of many years. In all published cases of CMV esophagitis with rheumatic diseases, there was also a high dosage of glucocorticoid medication. To avoid complications regular rheumatological screening controls and adjustment of immunosuppressive therapy are therefore important to maintain control of the disease with low dosage glucocorticoids.

Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: To investigate the correlation of serum levels of high mobility group box 1 (HMGB1) with the extent of granulomatous inflammation in granulomatosis with polyangiitis (GPA). METHODS: From 169 patients with GPA, 17 patients with granulomatous inflammation, without evidence of vasculitis were identified and 36 patients without measurable 'granuloma' formation. HMGB1 serum levels were determined and compared between the two groups, using a Mann-Whitney U test. Serum levels of 26 healthy individuals served as controls. In a further 21 patients with GPA with a pulmonary granulomatous manifestation from the study population, CT volumetry of 'granuloma' was performed. Volumes were compared with serum levels of HMGB1 (Spearman rank order test). RESULTS: Serum levels of HMGB1 were significantly higher in patients with predominant granulomatous disease than in patients without measurable 'granuloma' manifestations (6.44 ± 4.53 ng/ml vs 3.85 ± 2.88 ng/ml; p=0.0107). In both groups, levels of HMGB1 were significantly higher than in controls (2.34 ± 2.01 ng/ml; p<0.01). A positive correlation of HMGB1 serum levels with volumes of pulmonary 'granuloma' (r=0.761, p<0.0017) was seen. CONCLUSIONS: HMGB1 serum levels are significantly higher in GPA with predominant granulomatous manifestations and correlate with volumes of pulmonary 'granuloma'. HMGB1 may be used as a marker of the burden of granulomatous inflammation in GPA.