[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.

[Off-label biologic therapy of ANCA-associated and non-ANCA-associated small-vessel vasculitis : Efficacy and safety analysis of a national registry (GRAID2)]. / Off-label-Biologikatherapie von ANCA-assoziierten und nicht-ANCA-assoziierten Kleingefäßvaskulitiden : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

[S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. / S2e-Leitlinie: Therapie der rheumatoiden Arthritis mit krankheitsmodifizierenden Medikamenten.

BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

[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.

[Clinical Phenomenology of Autoimmune Encephalitis]. / Klinische Phänomenologie der Autoimmunenzephalitiden.

Antibody-associated disorders of the central nervous system constitute a heterogeneous group of disorders that can be roughly divided into two categories: Classic paraneoplastic syndromes associated with so-called well-characterized antibodies (paraneoplastic neurological disorders, PND) and autoimmune disorders with antibodies to membrane-bound or synaptic antigens (autoimmune encephalitis, AE). The discovery of autoimmune encephalitis has led to a paradigm shift in diagnosis and therapy as well as a reclassification of some neuropsychiatric syndromes that were previously classified as idiopathic or simply covered with descriptive terms.In this review article, especially clinical aspects of autoimmune encephalitis will be discussed, as there has been a rapid increase in knowledge in this regard within the past decade; increasingly overlap syndromes and associations with other disease entities have been detected. In addition to general aspects, characteristics of anti-NMDAR-, anti-LGI1-, anti-GABAA and GABABR, anti-AMPAR-, anti-CASPR2-, anti-mGluR, anti-GlycinR-, anti-GAD, anti- DPPX- and anti-D2 R encephalitis and the anti-IgLON5 encephalopathy will be presented.

[ANCA-associated vasculitis]. / ANCA-assoziierte Vaskulitiden.

The vasculitides represent one group of the systemic rheumatic diseases. Among the vasculitides we distinguish between large- (i.e. giant cell arteritis), medium- (i.e. polyarteritis nodosa) and small-vessel vasculitides (i.e. ANCA-associated vasculitides). Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the ANCA-associated vasculitides. They share the features of vasculitic manifestations in small- to medium-sized vessel beds (which can occur in almost any organ system) and the presence of ANCA, the detection of which, however, is not necessarily mandatory. The treatment of AAV depends on disease stage and activity and is carried out on the basis of randomized controlled trials with an initial regimen aimed at inducing remission followed by maintenance treatment. In addition to glucocorticoids, conventional immunosuppressants (such as methotrexate, azathioprine and cyclophosphamide) form the basis of treatment, whereby rituximab, first licensed for the treatment of severe active GPA and MPA in 2013, has emerged as new treatment option.

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.

[Genetic risk factors for vasculitis]. / Genetische Risikofaktoren von Vaskulitiden.

Among the vasculitides, genome-wide association studies (GWAS) have so far been performed for Behçet's disease, Kawasaki disease, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). These studies delivered valuable information with respect to the pathogenesis and therapeutic targets: Apart from HLA-B51 and HLA-A26, distinct polymorphisms in cytokine (IL-10) or cytokine receptor (IL-12R/IL-23R) genes, transcription factors (STAT4) and genes encoding for proteins involved in antigen presentation (ERAP-1) have been identified as risk factors for Behçet's disease. The results of two GWAS performed for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis GPA and MPA in Europe and the USA confirmed that the HLA-DP locus is the most relevant risk factor for GPA. Furthermore, the European GWAS confirmed SERPINA-1, a deficiency allele of the α-1-antitrypsin gene, as a genetic risk factor in GPA and identified a polymorphism in the proteinase 3 gene (PR3), one of the target antigens of ANCA, as a risk factor for GPA and PR3-ANCA-associated vasculitis.

[ANCA-associated vasculitis]. / ANCA ("anti-neutrophil cytoplasm antibody")-assoziierte Vaskulitiden.

Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV). They share the feature of vasculitic manifestations in small to medium-size vessel beds which can occur in nearly any organ system. The treatment of AAV is dependent on stage and activity and is carried out on the basis of randomized controlled trials with an initial remission induction regimen followed by maintenance treatment. Apart from glucocorticoids, conventional immunosuppressants are the basis of treatment whereby biologics, such as rituximab have emerged as new treatment options.

[Update on granulomatosis with polyangitis (GPA, Wegener's granulomatosis)]. / Update Granulomatose mit Polyangiitis (GPA, Wegener-Granulomatose).

Granulomatosis with polyangitis (GPA, Wegener's granulomatosis) is characterized by a granulomatous inflammation of the respiratory tract and a necrotizing ANCA-associated small to medium-size vessel vasculitis with a predilection for the lungs (pulmonary capillaritis) and kidneys (necrotizing glomerulonephritis). The disease evolves stage-wise and typically starts as inflammation of the respiratory tract followed by development of systemic vasculitis manifestations. Today, treatment is evidence-based and adapted according to activity and disease stage which has resulted in a significant improvement in long-term outcome. Early mortality during the first year of treatment poses one of the main problems and is a result of infections under immunosuppressive treatment. Furthermore, treatment of refractory disease activity which is often represented by granulomatous manifestations is still a challenge and may result in significant organ damage if not treated successfully.

[Neurological manifestations of vasculitis and primary central nervous system vasculitis]. / Neurologische Manifestationen von Vaskulitiden und primäre ZNS-Vaskulitis.

Neurologic complications of vasculitis occur frequently in the form of either peripheral neuropathy or manifestations within the central nervous system (CNS). Primary vasculitis of the CNS is characterized by central nervous system manifestations only with no evidence of systemic disease manifestations. Large vessel vasculitis is particularly associated with central nervous system complications, such as ischemic cerebral infarcts whereas medium size, e.g. polyarteritis nodosa and small vessel vasculitis, e.g. antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis manifest with peripheral neuropathies and central nervous system complications. The same also holds true for Behçet's disease which affects both large, medium and small sized arteries and veins. Due to the severity of nervous system manifestations a highly potent immunosuppressive therapy (e.g. cyclophosphamide and glucocorticoids) is usually required for remission induction. Virus-associated vasculitis (e.g. hepatitis C-associated cryoglobulinemic vasculitis) should receive antiviral therapy as first line treatment. Chronic damage is frequent in spite of swift initiation of immunosuppressive treatment.

ANCA-associated vasculitis is linked to carriage of the Z allele of α1 antitrypsin and its polymers.

BACKGROUND: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between α1AT and AAV. METHODS: The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.