Cord Sunderkoetter

Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells

Glucocorticoids (GC) are still the most widely used immunosuppressive agents in clinical medicine. Surprisingly, little is known about the mechanisms of GC action on monocytes, although these cells exert pro‐ and anti‐inflammatory effects. We have shown recently that GC induce a specific monocyte phenotype with anti‐inflammatory properties in humans. We now investigated whether this also applies for the murine system and how this subset would relate to recently defined murine subtypes. After treatment with dexamethasone for 48 h, monocytes up‐regulated scavenger receptor CD163 and Gr‐1, down‐regulated CX3CR1, and shared with human GC‐treated monocytes functional features such as low adhesiveness but high migratory capacity. They specifically up‐regulated anti‐inflammatory IL‐10, but not TGF‐β, and in contrast to their human counterparts, they down‐regulated IL‐6. Although GC‐induced monocytes down‐regulated CX3CR1, a distinctive marker for classical/proinflammatory human and murine monocytes (CX3CR1loCCR2+Ly6Chi), they differed from this physiologically occurring subset, as they remained Ly6Cmed and unactivated (CD62 ligand++). In addition to their immunosuppressive effects, they were CD11b+Gr‐1+ and expressed the IL‐4Rα chain (CD124), a recently described, signature molecule of tumor‐induced myeloid‐derived suppressor cells (MDSC). We therefore generated murine MDSC in B16 melanoma‐bearing mice and indeed found parallel up‐regulation of CD11b+Gr‐1+ and CD124 on GC‐induced monocytes and MDSC. These data allow us to speculate that the GC‐induced subtype shares with inflammatory monocytes the ability to migrate quickly into inflamed tissue, where they, however, exert anti‐inflammatory effects and that similarities between GC‐induced monocytes and MDSC may be involved in progression of some tumors observed in patients chronically treated with GC.

EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis

Objectives The systemic vasculitides are multiorgan diseases where early diagnosis and treatment can significantly improve outcomes. Robust nomenclature reduces diagnostic delay. However, key aspects of current nomenclature are widely perceived to be out of date, these include disease definitions, classification and diagnostic criteria. Therefore, the aim of the present work was to identify deficiencies and provide contemporary points to consider for the development of future definitions and criteria in systemic vasculitis. Methods The expert panel identified areas of concern within existing definitions/criteria. Consequently, a systematic literature review was undertaken looking to address these deficiencies and produce ‘points to consider’ in accordance with standardised European League Against Rheumatism (EULAR) operating procedures. In the absence of evidence, expert consensus was used. Results There was unanimous consensus for re-evaluating existing definitions and developing new criteria. A total of 17 points to consider were proposed, covering 6 main areas: biopsy, laboratory testing, diagnostic radiology, nosology, definitions and research agenda. Suggestions to improve and expand current definitions were described including the incorporation of anti-neutrophil cytoplasm antibody and aetiological factors, where known. The importance of biopsy in diagnosis and exclusion of mimics was highlighted, while equally emphasising its problems. Thus, the role of alternative diagnostic tools such as MRI, ultrasound and surrogate markers were also discussed. Finally, structures to develop future criteria were considered. Conclusions Limitations in current classification criteria and definitions for vasculitis have been identified and suggestions provided for improvement. Additionally it is proposed that, in combination with the updated evidence, these should form the basis of future attempts to develop and validate revised criteria and definitions of vasculitis.

High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy

IntroductionIn systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents.MethodsData on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS).ResultsA total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose ≥ 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties.ConclusionsDespite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.

Scalp necrosis in giant cell arteritis: Case report and review of the relevance of this cutaneous sign of large-vessel vasculitis

Giant cell arteritis (GCA) is a systemic vasculitis associated with severe complications such as loss of vision and, rarely, scalp necrosis. We present a patient with GCA who had bilateral scalp necrosis and an erythrocyte sedimentation rate of only 21 mm after the first hour. Therapy with systemic steroids, which were slowly tapered over 1 year, led to secondary wound healing without recurrence. As there are no systematic reviews on the occurrence of scalp necrosis in patients with GCA, we performed a literature research and meta-analysis and discovered 78 cases published between 1946 and 2007. Analysis of the data revealed that GCA with scalp necrosis is associated with a higher incidence of vision loss (32%) and other visual defects (37.3%) than GCA without scalp necrosis (visual disturbances in up to 20%). GCA with scalp necrosis is also associated with an increased mortality (standard mortality ratio [SMR], 4.2) in contrast to GCA without scalp necrosis, which has no significantly higher mortality than age-matched controls (SMR 0.8-1.034). In patients with scalp necrosis, the diagnosis of GCA was made about 1 month later than in patients without scalp necrosis, and scalp necrosis was never reported to occur after onset of therapy with glucocorticoids. Thus, for reasons beyond potential loss of vision, physicians should be alert for symptoms of GCA as only timely diagnosis and immediate therapy may prevent serious complications and increased mortality.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis

Background Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Methods The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Results Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often ‘other antibodies’ (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. Conclusions These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)–associated inflammatory diseases

BACKGROUND Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. RESULTS Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. CONCLUSION Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.

Induction of an anti-inflammatory human monocyte subtype is a unique property of glucocorticoids, but can be modified by IL-6 and IL-10.

Glucocorticoids (GC) are the most widely used immunosuppressive agents in clinical medicine. Recently we showed that GC enhance survival of human monocytes and induce a specific anti-inflammatory monocyte subtype which actively induces resolution of inflammation. We now investigated if cytokines IL-4, IL-6 and IL-10, which, like GC, have mostly anti-inflammatory effects on macrophages, would have GC-like effects also on monocytes. Human monocytes were stimulated with either cytokine, GC or combination thereof, and resulting effects on apoptosis, adherence, migration, phagocytosis, ROS production and cell surface phenotype were determined. We found that IL-4, IL-6, and IL-10 had either less or different effects on various anti-inflammatory functions of monocytes compared to GC. As such, IL-4 and IL-6 alone did not delay apoptosis while IL-10 even enhanced it. However, IL-6 or IL-10 increased GC-mediated protection from apoptosis when applied together with GC. Thus, the potential of GC to induce anti-inflammatory human monocytes is unique and not mimicked by the investigated cytokines. However, IL-6 and IL-10 amplify GC-induced anti-inflammatory and pro-resolution mechanisms by enhancing survival of GC-induced monocytes and thus sustaining their function. This combined effect of GC and cytokines could be important for the physiological switch from amplification towards resolution phase of inflammation.

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.

Objective. Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. Methods. The data of 3248 patients with SSc were analyzed. Results. Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. Conclusion. These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

PW02-018 - Impact of PSTPIP1 mutaions on clinical phenotype

Hyperzincaemia and hypercalprotectinaemia (Hz/Hc), a rare condition within the spectrum of autoinflammatory diseases, is associated with hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive. So far, no genetic cause has been identified. While the clinical appearance is heterogeneous, all affected individuals present with extremely elevated MRP8/MRP14 (calprotectin) serum concentrations (0.9-12.0 g/l (normal range < 0.001 g/l)).

AB0164 Disease Progression in 282 Patients with Undifferentiated SSc – Data from The German Network for Systemic Scleroderma

Background Systemic sclerosis (SSc) is a heterogeneous multisystem connective tissue disease, usually subdivided into the main SSc subsets, e.g. limited (lcSSc), diffuse SSc (dcSSc) and SSc overlap syndromes. However, some patients present with symptoms suggestive of, but not conclusive for a diagnosis of definite SSc. This subset has been referred to as undifferentiated or very early SSc. It was defined as positive RP together with at least one further feature of SSc and/or detectable SSc-specific autoantibodies. Objectives Methods Up to date, more than 3400 patients have been registered within the German network for systemic scleroderma. Disease progress after initial patient registration and further follow-up visits was analysed to determine, whether clinical features in patients with undifferentiated SSc change over time into definite SSc. Results Among 3473 registered patients, 8.1% (282/3473) were diagnosed with undifferentiated SSc. Of these, 87.5% were female with a mean age at onset of 59.9±1.5years. A significant difference was detectable comparing patients with undifferentiated SSc and lcSSc (54.8±0.5years; p<0.001) as well as dcSSc (49.8±0.6years; p<0.001). Positive antinuclear antibodies (ANA) were detectable in 219 (77.7%) patients; of these 40.2% were anti-centromer (ACA) positive and 12.8% anti-topoisomerase antibody (ATA) positive. No substantial difference regarding organ manifestations between patients with or without existing ANAs was found. 34.0% of undifferentiated SSc patients suffered from sicca symptoms, followed by 31.2% with gastrointestinal (GI) involvement, 30.5% with musculoskeletal involvement, 14.5% with lung fibrosis, 6.0% with heart involvement, 5.0% with pulmonary arterial hypertension (PAH) and 0.4% with renal crisis. Musculoskeletal involvement, sicca symptoms and heart involvement were found in a similar percentage in patients with undifferentiated and lcSSc. Lung fibrosis, PAH and GI involvement occurred significantly less in patients with undifferentiated SSc compared to lcSSc. Within a mean follow-up time of 3.6years, the majority of the patients classified initially as undifferentiated SSc, remained within this subset (76.6%), while only 16.3% converted into lcSSc. 4.6% were classified as dcSSc and 3.2% as SSc overlap syndromes. Conclusions Patients classified as undifferentiated SSc, develop clinical features suggestive of SSc at a significantly older age than other subsets (i.e. 5–10 years). During follow up progression into a limited, diffuse or SSc overlap syndrome subset was observed, however, the majority of undifferentiated SSc patients remained stable and did not develop definite SSc. Disclosure of Interest None declared