[Differential diagnosis of hypereosinophilia]. / Differenzialdiagnose der Hypereosinophilie.

Eosinophilia is defined as an elevated absolute number of eosinophilic leukocytes in peripheral blood or tissue. Its absolute number also defines the grade of eosinophilia. The main causes are allergic (including drug side effects) and infectious triggers but malignant and autoimmune diseases can also result in eosinophilia. Severe eosinophilia with the number of eosinophils >5000/µl are mostly caused by myeloproliferative disorders, eosinophilic granulomatosis with polyangiitis or during tissue migration in parasitic tissue infections. Hypereosinophilic syndrome is defined as eosinophilia with >1500 eosinophils/µl and a duration of more than 6 months by exclusion of parasitic infections, allergies or other causes of tissue eosinophilia with end-organ damage. For the diagnosis of a persistent eosinophilia a detailed medical history and physical examination should be followed by early organ screening, infection diagnostics especially for helminth infections and hematological laboratory analyses including bone marrow investigations.

[Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from a German registry (GRAID2)]. / Wirksamkeits- und Sicherheitsanalyse von Off-label-Biologikatherapien bei Patienten mit autoinflammatorischen Erkrankungen : Erfahrungen aus einem Deutschen Register (GRAID2).

OBJECTIVE: To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in a real-life setting in Germany. METHODS: The German Register of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with a biologic agent. RESULTS: Data from 26 patients with AIF and 5 with MAS were collected. Of the AIF patients 13 (50%) were diagnosed with adult onset Still's disease (AOSD), 6 (23%) with familial Mediterranean fever (FMF), 4 (15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1 (3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2 (8%) with undifferentiated fever syndromes. The 5 MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2 cases AOSD. In 1 patient a chronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6 cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had a moderate response. There were no non-responders. Within the group of AIF patients the physicians documented a very effective or effective treatment in 38.5%, a moderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5 of the MAS and in 92% of the AIF patients. CONCLUSION: The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

[Rituximab for the treatment of poly- and dermatomyositis : Results from the GRAID-2 registry]. / Rituximab zur Behandlung von Poly- und Dermatomyositis : Die Ergebnisse des GRAID-2-Registers.

INTRODUCTION: In the treatment of poly- and dermatomyositis, only a limited number of treatment modalities are established. OBJECTIVE: The goal of the GRAID-2 registry was to study off-label use of biologic drugs for this indication in Germany. PATIENTS AND METHODS: Analysis of the data of the GRAID-2 registry for poly- and dermatomyositis. RESULTS: In 22 of the 23 patients in the GRAID-2 registry, rituximab (RIX) was administered, while 1 patient was given tocilizumab as off-label therapy. The 22 patients who received RIX treatment were analyzed. At the start of treatment, the following active manifestations were present: myositis (n = 18), lung involvement (mainly interstitial lung disease; n = 10), arthritis (n = 10), skin manifestation (n = 9), and Raynaud syndrome (n = 5). Nine of the patients were Jo-1-antibody positive. All patients had previous treatments with multiple conventional immunosuppressive drugs. Treatment with RIX was given as infusions of 1 g i. v., which were repeated after 2 weeks. Patients received a mean of 3.09 ± 2.27 infusions (equivalent to 1.5 cycles of 2 × 1 g, max. 5 cycles). Tolerability of RIX treatment was rated as very good in 16 of 22 patients (72%), good in 5 (23%), and moderate in 1 (5%). In all, 27 adverse events were documented, with the majority being infections, whereby 2 severe infections occurred (6.59 per 100 patient-years). Eighty six percent of the patients showed complete remission of their myositis and 79% of their arthritis. The mean value of creatinine kinase in plasma fell from 1505 ± 2534 U/l before the start of treatment to 39 ± 134 U/l at the last visit. Regarding lung involvement, 1 of 10 of the patients showed complete and 6 of 10 partial remissions. In 2 of 10 patients, lung disease was stable during treatment. CONCLUSION: RIX is the preferred off-label biologic drug for poly- and dermatomyositis in Germany. In spite of a strongly pretreated group of patients, the tolerability is acceptable, although the patient number in this investigation is small. Moreover, the results lead to the assumption that the majority of the patients had a good or even very good therapeutic response to RIX.

[Off-label biological therapies in patients with large vessel vasculitis and/or polymyalgia rheumatica : Safety and efficacy analysis of a nationwide German registry (GRAID2)]. / Off-label-Biologikatherapie bei Patienten mit Großgefäßvaskulitiden und/oder Polymyalgia rheumatica : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the safety and clinical outcome of biological therapies in patients with large vessel vasculitis (LVV) or polymyalgia rheumatica (PMR) refractory to standard of care therapy in a real-life setting in Germany. METHODS: GRAID 2 (German Registry in Autoimmune Diseases 2) is a retrospective, noninterventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy treated with an initial off-label biological between August 2006 and December 2013. The retrospective documentation comprised case history, diagnosis, course of disease including safety and overall efficacy. RESULTS: Data from 14 patients were collected, 11 with LVV (78.6%) and 3 with isolated PMR (21.4%). Ten patients were treated with tocilizumab (71.4%), while 3 patients received infliximab infusions (21.4%) and 1 patient was treated with rituximab (7.1%). All clinical as well as laboratory efficacy parameters improved substantially. After the first application, tolerability of biologicals was assessed as "very good"/"good" by the physicians in 92.3% of the patients. Altogether, 8 adverse events (AEs) occurred in 4 patients including 3 infections (1 urogenital infection, 2 diverticulitis) representing a rate of 23.6 infections per 100 patient-years. One of these infections (diverticulitis under infliximab treatment) was rated as serious AE, requiring ICU treatment representing a rate of serious AEs of 7.9 per 100 patient-years. No deaths occurred during the observation period. CONCLUSION: With known limitations of a retrospective database, the results of this survey confirm data of smaller case series and proof-of-concept studies and suggest a substantial response to biological therapies in patients with otherwise refractory LVV or PMR with no new safety signals.

[Varicella gastritis under immunosuppression : Case report of a woman after lung transplantation due to granulomatosis with polyangiitis]. / Varizella-Gastritis unter Immunsuppression : Kasuistik einer Patientin nach Lungentransplantation bei Granulomatose mit Polyangiitis.

A 35-year-old woman who had previously undergone a lung transplantation presented with severe abdominal pain and vomiting. The gastroscopy showed diffuse ulcerative gastric lesions. Tests for varicella zoster virus and Epstein-Barr virus via polymerase chain reactions (PCR) on endoscopically obtained gastric biopsies were found to be positive and confirmed varicella gastritis. Intravenous antiviral therapy with acyclovir was administered resulting in a normalization of all clinical symptoms, especially of abdominal pain and inflammation parameters.

[Allogeneic stem cell transplantation : An option for autoimmune diseases?] / Allogene hämatopoetische Stammzelltransplantation : Eine Option bei Autoimmunerkrankungen?

According to experimental animal models and experiences of patients with coexisting autoimmune diseases, allogeneic stem cell transplantation has the potential to reestablish and maintain immunological tolerance. On the other hand, it is associated with significant treatment related mortality and may induce diverse immunological diseases by graft-versus-host reaction. Other than with severe aplastic anemia, it is not an established therapy for autoimmune diseases; it is under investigation in clinical trials and might be considered in severe, refractory immune cytopenia.

[Autologous stem cell transplantation in systemic sclerosis]. / Autologe Stammzelltransplantation bei systemischer Sklerose.

Autologous hematopoietic stem cell transplantation (HSCT) is a very effective treatment option for patients with severe systemic sclerosis (SSc). In addition to various case series two randomized controlled trials could prove its superiority over intense cyclophosphamide pulse therapy. Nevertheless, HSCT is associated with a treatment-related mortality of approximately 10 %; therefore, further studies should be carried out to reduce the toxicity of HSCT by adaptation of the therapy regimen and the option of HSCT should be made available earlier to patients with a high risk of mortality. The mechanism of action of HSCT is still poorly understood. While profibrotic cytokines or even autoantibodies hardly appear to be influenced by the treatment, alterations to regulatory T­cells may play a role. Further improvement of transplantation regimens as well as a better understanding of the underlying pathogenetic principles and mechanisms of action should be the aim of further studies on HSCT.

[Established medications : new areas of application]. / Etablierte Medikamente : Neue Einsatzgebiete.

During the last 10 years several new medications from hemato-oncology and transplantation medicine have been transferred to rheumatology. Additionally, medications which are approved for rheumatoid arthritis were increasingly also studied and used for other systemic inflammatory rheumatic diseases. This is especially the case for rituximab and mycophenolate and to a lesser extent also for leflunomide, tumor necrosis factor (TNF) antagonists, tocilizumab and abatacept. Recently, rituximab was approved for severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) after the publication of two prospective randomized trials in 2010. The situation concerning rituximab is much more problematic for systemic lupus erythematosus (SLE) where randomized placebo-controlled trials exist but unfortunately did not meet the primary endpoint requirements (too many highly effective additional forms of treatment in both arms and unsuitable endpoints), although data from registries suggest efficacy especially in cases resistant to treatment. In the case of mycophenolate (MPS) the problem with SLE is totally different. All prospective trials met the endpoints and in one trial MPS was even superior to azathioprine for treatment of lupus nephritis (LN) which led to the recommendation of MPS for induction and maintenance in LN by EULAR and EDTRA as well as more recently by the ACR. However, MPS still is not approved for SLE or LN. The present manuscript gives an overview of existing data for selected connective tissue diseases and vasculitides (for which at least larger retrospective case series or registry data exist) being treated with medications approved for other indications.

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.

Fertility preservation methods in young women with systemic lupus erythematosus prior to cytotoxic therapy: experiences from the FertiPROTEKT network.

OBJECTIVES: Despite new treatment options, some patients with systemic lupus erythematosus (SLE) need to be treated with the cytotoxic agent cyclophosphamide (CYC). Unlike malignant disease, there are no recommendations for ovarian protection in SLE. The clinical experience of the FertiPROTEKT network as well as recommendations after literature review will be presented in this paper. METHODS: Retrospective analyses of counselling and treatment data from the FertiPROTEKT register with special respect to SLE patients under 40 years prior to planned CYC treatment. RESULTS: A total of 2836 patients were advised prior to cytotoxic treatment in one of the FertiPROTEKT centres during January 2007 to November 2011. Of those, 68 patients (mean age 25 +/- 6.07 years) were counselled for severe SLE. Only five women did not make use of a fertility preservation method. Sixty-three patients (92.6%) decided in favour of a fertility preservation method. The largest proportion (91.2%) opted for treatment with a GnRH analogue. Ovarian tissue removal for cryoconservation was performed in 16 patients (25%). Stimulation therapy for cryoconservation of fertilized egg cells was performed in three patients (4.4%). CONCLUSIONS: When counselling patients with SLE for fertility preservation one has to be aware of the disease-specific risks. According to the literature, a safe and effective option in SLE up to now has been the use of a GnRH analogue. Cryoconservation of ovarian tissue must still be seen as an experimental treatment, but as data on removal, cryoconservation, retransplantation and pregnancies are steadily rising, this presents a promising option for young SLE patients. Cryoconservation of oocytes must be very critically evaluated due to the need for a stimulation therapy and should only be performed after particular consideration of the individual risks.

[Fertility preservation for young patients with autoimmune diseases and the need for cytotoxic treatment. Clinical experiences from interdisciplinary consultation]. / Fertilitätserhaltende Maßnahmen bei jungen Frauen mit Autoimmunerkrankung vor zytotoxischer Therapie : Erfahrungen aus einer interdisziplinären Sprechstunde.

In cases of severe exacerbation of autoimmune diseases (AID) cytotoxic therapy, in particular with cyclophosphamide (CYC) is needed. As the peak occurrence of such AIDs occurs in young women during the childbearing years, preservation of fertility and the hormonal function of the ovaries are an interdisciplinary challenge.For ovarian protection several options exist. Gonadotropin-releasing hormone analogues in parallel with CYC treatment seem to reduce the cytotoxic effect on the ovaries. Fertilized and unfertilized oocytes can be conserved by cryoconservation after ovarian stimulation. A relatively new strategy uses cryopreservation and autotransplantation of human ovarian tissue prior to cytotoxic therapy. As all these methods are accompanied with side-effects and possible delays in the necessary CYC treatment, a close collaboration of gynecologists and internists is needed. The decision for the optimal preservation therapy should always be based on the individual patient.

[18F] FDG-PET/CT as a new and sensitive imaging method for the diagnosis of large vessel vasculitis.

OBJECTIVE: To determine the value of the new imaging modality positron-emission tomography/computed tomography (PET/CT) for the diagnosis and re-evaluation of large vessel vasculitis. METHODS: Thirteen patients newly diagnosed or re-evaluated for suspected clinical disease activity of Takayasu arteritis (TA, 3 patients) or giant cell arteritis (GCA, 10 patients) underwent PET/CT. Clinical activity status, serological markers, and alternative imaging methods were evaluated. RESULTS: In patients with clinical activity despite nearly normal erythrocyte sedimentation rate (ESR) and C reactive protein (CRP), disease activity could be shown by PET-CT. A long segmental, increased fluoro-deoxyglucose (FDG) uptake in the vessel wall served as confirmation of the vascular inflammation. The aortic arch was involved in all patients with active disease (n=12). In the complementary CT scans, stenotic lesions were found in 8 out of 13 patients. Duplex ultrasonography was performed in 11/13 patients and was positive in nine of these patients at least at one site. Magnetic resonance imaging (MRI) was done for confirmation in 10 patients. CONCLUSION: Doppler ultrasonography is a very useful and widely available method to confirm a first suspicion of vasculitis, but it has limitations especially at the large thoracic vessels, which are affected in many cases. ESR and CRP alone are not sufficient to evaluate disease activity. The new imaging modality PET/CT provides the additional information. It allows the evaluation of disease activity and vessel morphology as well as the localization of the inflammatory process in the same session.

Rituximab for treatment-resistant extensive Wegener's granulomatosis--additive effects of a maintenance treatment with leflunomide.

Extensive Wegener's granulomatosis (WG) is treated by glucocorticosteroids (GC) and cyclophosphamide (CYC). In some cases, the disease is refractory to CYC. For those patients the depletion of B-lymphocytes with rituximab is a promising new treatment modality. This is a retrospective study of six patients receiving rituximab (RTX) with 4 x 375 mg/m(2) body surface weekly because of inefficacy of CYC. Proteinase-3-antineutrophil cytoplasmic antibodies (PR3-ANCA) and c-ANCAs were assessed. For clinical follow-up the Birmingham Vasculitis Activity Score for WG (BVAS/WG) was used. In five of the six cases, leflunomide (LEF) was given as maintenance treatment. Mean follow up was 16 months (12-21 months). The median PR3-ANCA titer fell from 36.8 U/ml at baseline to 21.4 U/ml after 3 months, 8.3 after 6 months, and 4.3 at month 12. The median BVAS/WG at baseline was 5 and 0 after 1 month. Two minor relapses could be noticed at month 3. After 6 months, one patient still had a BVAS of 1, all the others had a BVAS of 0. At month 18, a major relapse occurred in one patient, which was successfully retreated with RTX. The RTX infusions were well tolerated. Rituximab is a well-tolerated, very effective medication for patients with Wegener's granulomatosis. Leflunomide maintenance may increase the efficacy of rituximab and prolong the disease-free period.

B-cell depletion in patients with rheumatoid arthritis refractant to multiple TNF blockers and the interleukin 1 receptor-antagonist anakinra. Good responses in an extreme negative selection.

To evaluate the efficacy of Rituximab in a negatively selected patient cohort, with inadequate response to different disease modifying drugs (DMARDs) and to at least two biologicals. Fifteen patients with severe rheumatoid arthritis with inefficacy of an average of 5 DMARDS and 2.5 TNF antagonists were treated with Rituximab. Eight patients were ineffectively pretreated with Anakinra as well. The disease activity score (DAS28) and the morning stiffness served for assessment of the clinical response. For maintenance treatment different conventional DMARDs were used (4xMTX, 4xLeflunomide, 1xmycophenolate, 1xsirolimus, 1xhydroxychloroquine). At baseline visit the mean DAS 28 was 5.9. The mean duration of morning stiffness was 99.6 min. At month 6 the mean DAS28 was 3.95. Forty percent (6 patients) showed a good and 33% (5 patients) a moderate response. Morning stiffness improved to 43 min. In this negatively selected group of patients Rituximab was safe and effective.