Interleukin-6 Blockade Research Articles

Abstract B60: Interleukin-1 expression and inflammasome activation in human malignant glioma

Abstract Introduction: Interleukin 1 (IL-1) is a major proinflammatory cytokine produced by myeloid cells and is implicated in neurodegeneration. In human brain, IL-1 is expressed by microglia and contributes to neuroinflammation and neuronal toxicity. IL-1 is also the major activator of human astrocyte and glioma cells. In this study, we investigated the mechanism of IL-1 α and IL-1β expression and activation in human glioma cells. Methods: Human glioblastoma cell lines (U87, U251, and SN19) as well as patient-derived glioma cell lines were stimulated with cytokines (IL-1/IFNγ) or TLR ligands (LPS or poly IC) and the expression of IL-1α and IL-1β was studied by real-time PCR, western blot analysis, and ELISA. The glioma secretome was investigated using quantitative mass spectrometry. Results: We found that while primary human astrocytes show IL-1 translational block (no protein made despite high level of mRNA), but GBM cells responded strongly to IL-1 itself to produce large amounts of IL-1α and IL-1β mRNA and proteins. Furthermore, GBM cells processed pro-IL-1β (31kDa) to mature IL-1β (17kDa) by activating the NALP3 inflammasome. Both ATP and nigericin induced IL-1β processing by upregulating NALP3. Proteomics analysis of IL-1 stimulated GBM cell secretome revealed several highly upregulated proteins (IL-8, MCP-1, tenascin-C, pentraxin 3, galectin 1, and MMP2), all of which are implicated in glioma progression. Furthermore, many extracellular matrix proteins (ECM) and ECM-related proteins were downregulated by IL-1 in the glioma secretome. Discussion: We propose that the ability of malignant glioma cells to produce IL-1 protein can set off chronic smoldering inflammation and induce epithelial-mesenchymal transition (EMT) resulting in increased migratory capacity, a unique gene signature, and increased immune signaling (NF-κB, pStat3). There is potential for IL-1 to be a biomarker/surrogate marker for a subset of GBM and that IL-1 blockade could benefit GBM patients. Citation Format: Leonid Tarassishin, Jihyeon Lim, Sunhee C. Lee. Interleukin-1 expression and inflammasome activation in human malignant glioma. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B60.

Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice

Non-alcoholic fatty liver disease (NAFLD) is hepatic manifestation of a metabolic syndrome and includes a spectrum of hepatic steatosis, steatohepatitis, and fibrosis. Interleukin-17 (IL-17) has been reported to play a critical role in inflammatory progression of some liver diseases. The present study was designed to investigate the role of IL-17 on high fat diet-induced NAFLD in C57BL/6 mice. IL-17 blockade with anti-IL-17mAb significantly improved liver function, attenuated hepatic lipid accumulation, suppressed Kuffer cells activation, and decreased pro-inflammatory cytokines levels, which were associated with inhibition of NF-κB signaling cascades activation. Our data suggested that IL-17 was related to disease progression in NAFLD mouse model and blocking IL-17 may be a promising novel therapeutic approach for patients with NAFLD.

Intra-Hippocampal Transplantation of Neural Precursor Cells with Transgenic Over-Expression of IL-1 Receptor Antagonist Rescues Memory and Neurogenesis Impairments in an Alzheimer’s Disease Model

Ample evidence implicates neuroinflammatory processes in the etiology and progression of Alzheimer's disease (AD). To assess the specific role of the pro-inflammatory cytokine interleukin-1 (IL-1) in AD we examined the effects of intra-hippocampal transplantation of neural precursor cells (NPCs) with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) on memory functioning and neurogenesis in a murine model of AD (Tg2576 mice). WT NPCs- or sham-transplanted Tg2576 mice, as well as naive Tg2576 and WT mice served as controls. To assess the net effect of IL-1 blockade (not in the context of NPCs transplantation), we also examined the effects of chronic (4 weeks) intra-cerebroventricular (i.c.v.) administration of IL-1ra. We report that 12-month-old Tg2576 mice exhibited increased mRNA expression of hippocampal IL-1β, along with severe disturbances in hippocampal-dependent contextual and spatial memory as well as in neurogenesis. Transplantation of IL-1raTG NPCs 1 month before the neurobehavioral testing completely rescued these disturbances and significantly increased the number of endogenous hippocampal cells expressing the plasticity-related molecule BDNF. Similar, but less-robust effects were also produced by transplantation of WT NPCs and by i.c.v. IL-1ra administration. NPCs transplantation produced alterations in hippocampal plaque formation and microglial status, which were not clearly correlated with the cognitive effects of this procedure. The results indicate that elevated levels of hippocampal IL-1 are causally related to some AD-associated memory disturbances, and provide the first example for the potential use of genetically manipulated NPCs with anti-inflammatory properties in the treatment of AD.

Interleukin-1 blockade in refractory giant cell arteritis

Giant cell arteritis is a primary large-vessel vasculitis characterized by an arterial wall inflammation associated with intimal hyperplasia leading to arterial occlusion. Glucocorticoids remain the mainstay of giant cell arteritis treatment. However, relapses and glucocorticoid-related complications are frequent and therapeutic options for refractory giant cell arteritis are quite limited. Like tumor necrosis factor-α and interleukin-6, interleukin-1β is also highly expressed in inflamed arterial walls of patients with giant cell arteritis and may contribute in the pathogenesis of this disease. We report treatment of three cases of refractory giant cell arteritis successfully treated with anakinra, an interleukin-1 blockade therapy. Anakinra was effective for all patients, yielding improvement in their inflammation biomarkers and/or in their symptoms, as well as a disappearance of arterial inflammation in PET/CT for two of them.

Thrombocytosis as a Response to High Interleukin-6 Levels in cGMP-Dependent Protein Kinase I Mutant Mice

The purpose of this study was to investigate the influence of cGMP-dependent kinase I (cGKI) on platelet production. We used hematology analyser to measure platelet counts in conventional cGKI-null mutants (cGKI(L1/L1)), gene-targeted cGKIα/β rescue mice (referred to as cGKI-smooth muscle [SM]) in which cGKI expression is specifically restored only in SM, platelet factor 4-Cre(tg/+); cGKI(L2/L2) mice in which the cGKI protein was specifically deleted in the megakaryocyte/platelet lineage and cGKI-deficient bone marrow-chimeras. Thrombocytosis was detected in cGKI(L1/L1) and in cGKI-SM. In contrast, neither platelet factor 4-Cre(tg/+); cGKI(L2/L2) nor cGKI-deficient bone marrow-chimeras displayed a thrombocytosis phenotype, indicating that the high platelet count in cGKI(L1/L1) and cGKI-SM mutants is attributable to loss of an extrinsic signal rather than reflecting an intrinsic defect in megakaryopoiesis. Cytometric analyses further showed that stimulation of bone marrow-derived wild-type megakaryocytes in vitro using serum preparations obtained from cGKI-SM mutants strongly accelerated megakaryopoiesis, suggesting that the high platelet count develops in response to serum factors. Indeed, using ELISA assay, we found elevated levels of interleukin-6, a known stimulator of thrombopoiesis, in cGKI-SM mutant serum, whereas interleukin-6 levels were unaltered in platelet factor 4-Cre(tg/+); cGKI(L2/L2) mice and cGKI-deficient bone marrow-chimeras. Accordingly, antibody-mediated blockade of interleukin-6 normalized platelet counts in cGKI-SM mice. Abnormal cGMP/cGKI signaling in nonhematopoietic cells affects thrombopoiesis via elevated interleukin-6 production and results in thrombocytosis in vivo. Dysfunction of cGMP/cGKI signaling in nonhematopoietic cells contributes to a high platelet count, which is potentially associated with thrombosis.

THU0079 Anti-IL-6 Receptor Antibody Suppresses Systemic Bone Loss by not Only Normalizing Bone Resorption but also Enhancing Bone Formation in a Mouse Model of Collagen-Induced Arthritis

BackgroundPatients with rheumatoid arthritis (RA) have a high risk of osteoporosis and osteoporotic fracture. In primary osteoporosis (either high bone turnover osteoporosis [type I] or low bone turnover osteoporosis [type...

AB0158 Anti-interleukin-6 receptor antibody suppresses loss of trabecular bone volume in mice with glucose-6-phosphate isomerase-induced arthritis

BackgroundOsteoporosis can lead to increased risk of fractures, which are associated with increased morbidity and mortality. The incidence rate of osteoporosis in patients with RA is several times that in...

AB1147 Treatment of blau syndrome-related uveitis with the long-acting IL-1 inhibitor CANAKINUMAB: 6 months follow-up

BackgroundPediatric granulomatousarthritis is a very rare conditionthataffectsyoung children and is characterized by the triad of exudative tenosynovitis, maculopapular rash, and uveitis. A genetic form, known as Blau syndrome (BS) is...

AB0743 Efficacy of anti-interleukin-6 receptor antibody (tocilizumab) in colombian patients with takayasu’s arteritis

BackgroundTakayasu’s arteritis (TA) is a chronic vasculitis that involves aorta and its main branches, where interleukin-6 (IL-6) seems to play a pathogenic role (1,2). The effect in four patients treated...

Spdef Null Mice Lack Conjunctival Goblet Cells and Provide a Model of Dry Eye

Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef(-/-) mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef(-/-) mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef(-/-) mice revealed down-regulation of goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef(-/-) mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease.

Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide stimulated BV2 microglial cells

Wogonin is a flavonoid compound which exhibits antioxidation, anti-inflammation, neuroprotection, and antitumorgenesis functions. However, the mechanism of how wogonin reduces proinflammatory cytokine generation in activated microglia is unclear. At present, we found wogonin inhibited lipopolysaccharide (LPS)-/interferon-γ (INF-γ)-induced generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Wogonin exhibited parallel inhibition on LPS-/INF-γ-induced expression of IL-6 and TNF-α messenger RNA at the same concentration range. LPS-/INF-γ-induced phosphorylation of signal transduction and transcription 1 and 3 (STAT1/3) were also inhibited by wogonin. Although wogonin expressed only weak inhibitory effect on LPS-/INF-γ-induced phosphorylation of Janus kinase-2 (Jak-2) and tyrosine kinase (Tyk)-2, it significantly attenuated the phosphorylation of Jak-1 and Jak-3. These results indicated that the blockade of IL-6 and TNF-α production by wogonin in LPS-/INF-γ-stimulated BV2 microglial cells was attributed mainly to the interference in Jak-1/-3-STAT1/3 signaling pathway.

Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. National Institutes of Health and Juvenile Diabetes Research Foundation.

Antizytokintherapie

Anticytokine therapies have revolutionized the treatment of chronic inflammatory diseases, particularly autoimmune diseases such as rheumatoid arthritis. As the first introduced principle of cytokine blockade in the 1990s, tumor necrosis factor (TNF)-α antagonists still represent the leading anticytokine therapy. There are currently five TNF antagonists available with indications in the fields of rheumatology, dermatology, and gastroenterology. Other therapeutic approaches have been introduced in the last 10 years, e.g., the blockade of interleukin (IL)-1, IL-6, and IL-12/23. The advantages of cytokine blockers are their rapid onset of action with high response rates and a tolerable safety profile. Nevertheless, anticytokine therapy can cause increased rates of tuberculosis and hepatitis B infections or reactivation. An appropriate screening before therapy is mandatory, and thorough monitoring of the disease course before and during therapy is also important. The development of further anticytokine drugs for the induction and maintenance of remission is, therefore, required.

Effects of Interleukin-1 Blockade With Anakinra on Adverse Cardiac Remodeling and Heart Failure After Acute Myocardial Infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) Pilot Study

A first pilot study of interleukin-1 blockade in ST-segment elevation acute myocardial infarction showed improved remodeling. In the present second pilot study, we enrolled 30 patients with clinically stable ST-segment elevation acute myocardial infarction randomized to anakinra, recombinant interleukin-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blind fashion. The primary end point was the difference in the interval change in left ventricular (LV) end-systolic volume index between the 2 groups within 10 to 14 weeks. The secondary end points included changes in the LV end-diastolic volume index, LV ejection fraction, and C-reactive protein levels. No significant changes in end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction were seen in the placebo group. Compared to placebo, treatment with anakinra led to no measurable differences in these parameters. Anakinra significantly blunted the increase in C-reactive protein between admission and 72 hours (+0.8 mg/dl, interquartile range-6.4 to+4.2, vs+21.1 mg/dl, interquartile range+8.7 to+36.6, p= 0.002), which correlated with the changes in LV end-diastolic volume index and LV end-systolic volume index at 10 to 14weeks (R=+0.83, p= 0.002, and R=+0.55, p= 0.077, respectively). One patient in the placebo group (7%) died. One patient (7%) in the anakinra group developed recurrent acute myocardial infarction. More patients were diagnosed with new-onset heartfailure in the placebo group (4, 27%) than in the anakinra group (1, 7%; p= 0.13). When the data were pooled with those from the first Virginia Commonwealth University-Anakinra Remodeling Trial (n= 40), this difference reached statistical significance (30% vs 5%, p= 0.035). In conclusion, interleukin-1 blockade with anakinra blunted the acute inflammatory response associated with ST-segment elevation acute myocardial infarction. Although it failed to show a statistically significant effect on LV end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction in this cohort of clinically stable patients with near-normal LV dimensions and function, anakinra led to a numerically lower incidence of heart failure.

Clinical and transcriptional response to the long‐acting interleukin‐1 blocker canakinumab in Blau syndrome–related uveitis

To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment. A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month. Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patient's blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes. The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments.

The heart on fire: inflammasome and cardiomyopathy

The heart on fire: inflammasome and cardiomyopathy

Blockade of Interleukin-33 Attenuates Allergic Contact Dermatitis in Model Mice: Possible Mechanism via Eosinophil Infiltration

Background: Interleukin (IL)-33, a novel member of the IL-1 family, is mainly produced by epithelial cells and endothelial cells. Effects of IL-33 on allergic diseases have been reported. Allergic contact dermatitis is a clinical form of contact hypersensitivity that involves a delayed-type hypersensitivity reaction. We previously reported that IL-33 is induced by tumor necrosis factor-alpha and interferon-gamma in keratinocytes and plays a critical role in allergic contact dermatitis. However, the mechanism underlying how IL-33 is involved in the pathogenesis of allergic contact dermatitis is not fully understood. We investigated the role of IL-33 in allergic contact dermatitis using model mice. Methods: Allergic contact dermatitis model mice were generated. Epidermal thickness and eosinophil infiltration in the dermis were evaluated by histology. The function of IL-33 was investigated by in vivo administration of an anti-IL-33 antibody. Results: Epidermal thickness was increased in the ear lesions of allergic contact dermatitis model mice. We showed that eosinophil infiltration in the dermis was increased in the ear lesions. We further found that blockade of IL- 33 attenuated not only the epidermal thickness but also the eosinophil infiltration in the dermis in the ear lesions. Conclusions: IL-33 may promote inflammation via eosinophil infiltration in allergic contact dermatitis. Blockade of IL-33 may represent a novel and potent therapeutic strategy for allergic contact dermatitis.

Interleukin-6; pathogenesis and treatment of autoimmune inflammatory diseases

Interleukin-6 (IL-6), originally identified as a B cell stimulatory factor-2, is a typical cytokine featuring redundancy and pleiotropic activity. A transient expression of IL-6 participates in host defense against acute environmental stress such as infections and injuries by activating immune responses, hematopoiesis and acute phase reactions. However, its abnormal, persistent production plays an important pathological role in the development of various autoimmune inflammatory diseases, so that it was hypothesized that IL-6 blockade would constitute a novel strategy for the treatment of such diseases and to this purpose tocilizumab, a humanized antiIL-6 receptor monoclonal antibody, was developed. Clinical trials have indeed proved the efficacy and tolerable safety of tocilizumab for patients with moderate to severe rheumatoid arthritis, and it is now used as a“ “ “ “made-in-Japan”innovative biologic for rheumatoid arthritis in more than 90 countries worldwide, as well as for patients with Castleman's disease and systemic and polyarticular juvenile idiopathic arthritis. Moreover, favorable results of recent clinical trials or case reports of off-label use with tocilizumab indicate that it is likely to be broadly applicable for the treatment of various autoimmune inflammatory diseases. Its wider application for various diseases as well as clarification of the mechanism(s) through which IL-6 blockade becomes clinically efficacious and of the etiology of dysregulated persistent IL-6 production in such diseases are important issues for future studies.

Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome

Mutations in SLC29A3 lead to pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy plus syndrome. We report a new association of PHID syndrome with severe systemic inflammation, scleroderma-like changes, and cardiomyopathy. A 12-year-old girl with PHID syndrome presented with shortness of breath, hepatosplenomegaly, and raised erythrocyte sedimentation rate and C-reactive protein. An echocardiogram showed biventricular myocardial hypertrophy, and cardiac magnetic resonance imaging showed circumferential late gadolinium enhancement of the myocardium. No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan. Abdominal ultrasound revealed intra-abdominal fat surrounding the solid organs, suggesting a possibility of evolving lipodystrophy with visceral adiposity. PHID syndrome is a novel monogenic autoinflammatory syndrome (AIS) associated with severe elevation of serum amyloid. Lipodystrophy, cutaneous sclerodermatous changes, and cardiomyopathy were also present in this case. In contrast to other AIS, blockade of interleukin-1 and tumor necrosis-α was ineffective.

Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens

ObjectivesMuckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1β monoclonal antibody, can abolish excess IL-1β. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies.MethodsTwo cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed.ResultsThe study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles.ConclusionsIL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.