Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study.

BACKGROUND: Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, which is currently under investigation for treatment of moderate-to-severe plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL-17 inhibitors for psoriasis. OBJECTIVES: To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies. METHODS: Forty-nine patients with moderate-to-severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28. RESULTS: At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated with nonlesional skin. CONCLUSIONS: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.

Dysregulated Fcγ receptor IIa-induced cytokine production in dendritic cells of lupus nephritis patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN-stimulating pathways, but also from decreased activation of type I IFN-inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR-induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR-mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR-induced interleukin (IL)-1ß production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR-mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL-1ß. This dysregulation may contribute to the development of nephritis in SLE patients.

Beneficial Immune Effects of Myeloid-Related Proteins in Kidney Transplant Rejection.

Acute rejection is a risk factor for inferior long-term kidney transplant survival. Although T cell immunity is considered the main effector in clinical acute rejection, the role of myeloid cells is less clear. Expression of S100 calcium-binding protein A8 (S100A8) and S100A9 was evaluated in 303 biopsies before and after transplantation from 190 patients. In two independent cohorts of patients with acute rejection (n = 98 and n = 11; mostly cellular rejections), high expression of S100 calcium-binding protein A8 (S100A8) and A9 (S100A9) was related to improved graft outcome. Mechanisms of action of the S100 molecules were investigated. In the graft and peripheral blood cells, S100A8 and S100A9 expression correlated with myeloid-derived suppressor markers. In line with this finding, recombinant S100A8 and S100A9 proteins inhibited maturation and the allogeneic T cell stimulatory capacity of dendritic cells. S100A9 enhanced the production of reactive oxygen species by macrophages, which suppressed T cell activity at low concentrations in the form of hydrogen peroxide. Intragraft S100A8 and S100A9 expression linked to reduced expression of T cell immunity and tissue injury markers and higher expression of immune regulatory molecules. This study sheds new light on the importance of myeloid cell subsets in directing the outcome of T cell-mediated acute rejection.

Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease.

OBJECTIVE: To profile quantitatively the T-cell repertoire in multiple joints and peripheral blood of patients with recent onset (early) or established rheumatoid arthritis (RA) using a novel next-generation sequencing protocol to identify potential autoreactive clones. METHODS: Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC). RESULTS: In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2-70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5-24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28-40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0-8%) between synovium and blood (p=0.01). CONCLUSIONS: In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.

New-onset polyarthritis during successful treatment of hidradenitis suppurativa with infliximab.

BACKGROUND: Hidradenitis suppurativa (HS) can be associated with several forms of arthritis, usually considered as reactive arthritis. A new observation is that some patients with HS develop arthritis after treatment with infliximab (antitumour necrosis factor-α). OBJECTIVES: A retrospective study was performed to establish the frequency and clinical presentation of new-onset arthritis during infliximab treatment. METHODS: Between 2005 and 2009, 27 individuals with severe HS were treated with infliximab and followed up closely. Laboratory parameters and side-effects were recorded. The frequency of arthritis was compared with control groups consisting of 227 patients with HS not treated with any biological, 22 patients with HS treated with adalimumab and 28 patients with psoriasis treated with infliximab, in the same period at the same clinic. RESULTS: Five of the 27 patients with HS (18%) treated with infliximab developed an acute and painful polyarthritis during treatment. The arthritis occurred on average after 12 months of treatment, was not clearly associated with anti-infliximab antibodies and resolved on average after 4 months. Interestingly, none of the patients had suffered from arthritis before despite the long duration of HS and all showed a good skin response to infliximab. Moreover, arthritis was not observed in any of the control groups. Compared with the adalimumab group and the psoriasis group, odds ratios of 7·241 [95% confidence interval (CI) 1·15-45·6] and 9·025 (95% CI 1·45-55·82) were calculated. CONCLUSIONS: The five cases described in this article suggest that infliximab treatment in HS can induce a transient but severe polyarthritis. The underlying mechanisms remain to be investigated further.

Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade.

OBJECTIVE: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis. METHODS: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry. RESULTS: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment. CONCLUSION: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.

Melanoma inhibitory activity, a biomarker related to chondrocyte anabolism, is reversibly suppressed by proinflammatory cytokines in rheumatoid arthritis.

OBJECTIVE: In mice, melanoma inhibitory activity (MIA) is a chondrocyte-specific molecule with similar regulation to collagen type II. As MIA is a small secreted protein, its value as cartilage biomarker in human inflammatory arthritis was assessed. METHODS: MIA tissue distribution was studied by quantitative PCR and immunohistochemistry. The regulation of MIA production was studied in vivo in rheumatoid arthritis (RA) (n = 37) and spondyloarthritis (SpA) (n = 30) synovial fluid (SF), and in vitro in alginate embedded human chondrocytes. Therapeutic modulation of serum MIA was evaluated during tumour necrosis factor (TNF)alpha and interleukin (IL)1 blockade in RA. RESULTS: MIA was primarily expressed by chondrocytes in the human joint. SF MIA levels were lower in RA than in SpA despite similar levels of overall synovial inflammation. Further analysis indicated that these levels were inversely correlated with the degree of joint inflammation in RA, but not in SpA, and that the levels of TNFalpha and IL1beta were significantly increased in RA versus SpA. Accordingly, these proinflammatory cytokines suppressed MIA mRNA and protein in cultured chondrocytes. This suppression was paralleled by suppression of cartilage anabolism as assessed by collagen type 2 and aggrecan mRNA. Treatment of patients with RA with TNF blockade or IL1 blockade induced an increase of serum MIA levels. CONCLUSION: The decreased levels of MIA in the inflamed RA joint and the coregulation of MIA and cartilage matrix molecules by proinflammatory cytokines indicate that joint inflammation in RA not only drives accelerated cartilage degradation but also suppresses cartilage anabolism. This inflammation-driven suppression is reversible in vivo.

Differences in pathophysiology between rheumatoid arthritis and ankylosing spondylitis.

Rheumatoid arthritis and ankylosing spondylitis are common and severe chronic inflammatory skeletal diseases. Recognizing the differences rather than emphasizing similarities is important for a better understanding of the disease processes, the identification of specific therapeutic targets and in the long-term better treatment options for the individual patients. We discuss a number of pathophysiological differences between rheumatoid arthritis and ankylosing spondylitis by looking at the anatomical characteristics, differences and similarities in the autoimmune and autoinflammatory reactions, association with other immune mediated inflammatory diseases, structural outcome, and their potential significance for further therapeutic developments. Further research into the differences between these diseases should focus on the specific nature of the immune/inflammatory components, the role of resident cells in the joint and joint-associated tissues, the types and mechanisms of tissue remodeling and the characteristics of the articular cartilage. Better insights into their individual characteristics may lead to better therapeutic strategies, specific targets and useful biomarkers.

An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis - A proof of concept trial.

OBJECTIVES: The primary objective of this trial was to assess safety and anti-inflammatory effects of an add-on training program involving breathing exercises, cold exposure, and meditation in patients with axial spondyloarthritis. METHODS: This study was an open-label, randomised, one-way crossover clinical proof-of-concept trial. Twenty-four patients with moderately active axial spondyloarthritis(ASDAS >2.1) and hs-CRP ≥5mg/L were included and randomised to an intervention (n = 13) and control group (n = 11) group that additionally received the intervention after the control period. The intervention period lasted for 8 weeks. The primary endpoint was safety, secondary endpoints were change in hs-CRP, serum calprotectin levels and ESR over the 8-week period. Exploratory endpoints included disease activity measured by ASDAS-CRP and BASDAI, quality of life (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS). RESULTS: We found no significant differences in adverse events between groups, with one serious adverse event occurring 8 weeks after end of the intervention and judged 'unrelated'. During the 8-week intervention period, there was a significant decline of ESR from (median [interquartile range] to 16 [9-26.5] to 9 [5-23] mm/hr, p = 0.040, whereas no effect was found in the control group (from 14 [8.3-27.3] to 16 [5-37] m/hr, p = 0.406). ASDAS-CRP declined from 3.1 [2.5-3.6] to 2.3 [1.9-3.2] in the intervention group (p = 0.044). A similar trend was observed for serum calprotectin (p = 0.064 in the intervention group versus p = 0.182 in the control group), but not for hs-CRP. CONCLUSIONS: This proof-of-concept study in axial spondyloarthritis met its primary endpoint with no safety signals during the intervention. There was a significant decrease in ESR levels and ASDAS-CRP upon the add-on training program in the intervention group. These findings warrant full-scale randomised controlled trials of this novel therapeutic approach in patients with inflammatory conditions. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02744014.

Tumour necrosis factor blockade increases lymphangiogenesis in murine and human arthritic joints.

OBJECTIVE: To investigate the presence and regulation of lymphatic vessels in inflamed joints of mice with experimental arthritis as well as patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS: Lymphatic vessels and blood vessels were assessed in synovial tissue of human tumour necrosis factor transgenic (TNFtg) mice and synovial biopsies from patients with RA and SpA by immunohistochemistry for podoplanin and CD31, respectively. Assessments were performed before and after TNF blockade in all biopsies. RESULTS: Lymphatic vessels were abundantly present in the synovial tissue of hTNFtg mice as well as patients with RA and SpA. The number of lymphatic vessels was positively related to the severity of synovial inflammation. Treatment with infliximab led to an increase in the formation of lymphatic vessels in murine and human inflammatory tissue. CONCLUSIONS: This study shows that TNF blockade promotes the proliferation of lymphatic vessels in the inflamed synovium of RA and SpA. This finding leads to the assumption that promotion of lymphangiogenesis may play an important part in efflux of cells and fluid out of the inflamed tissue.

A functional polymorphism of TIR-domain-containing adaptor protein is not associated with axial spondyloarthritis.

OBJECTIVE: A genetic variant of the toll-like receptor (TLR)2/4 adaptor protein TIRAP (single nucleotide polymorphism (SNP) C539T) was identified in a UK and in several African populations. The heterozygous genotype of this SNP has been associated with protection from severe infections. This allele results in an attenuated response to bacterial pathogens. As an exaggerated innate immune response to pathogens has been implicated in spondyloarthritis (SpA) pathogenesis, we analysed if the heterozygous C/T genotype was underrepresented in axial SpA compared with healthy controls. METHODS: 204 patients with axial SpA and 175 population-matched controls were included. SNP C539T was determined with a sequence-specific polymerase chain reaction and direct sequencing. RESULTS: The frequency of the haplotypes was similar in cases and controls (87% for C and 13% for T in both groups). The C/T genotype, which attenuates TLR signalling, was not underrepresented in cases versus controls (19% in controls vs 24% in cases, p = 0.44). The T/T genotype, was slightly lower in cases than in controls, although this was not significant (3.4% in controls vs 1% in cases, p = 0.15). Within the cases, there were no differences in disease phenotype or activity between patients with the C/C or C/T genotype. CONCLUSIONS: This study did not show significant associations of SNP S180L of the TLR2/4 adaptor protein TIRAP with axial SpA.

Chemical agents and enzymes used for the extraction of gut lymphocytes influence flow cytometric detection of T cell surface markers.

Chemical agents (DTT, EDTA) and enzymes (collagenase, DNAse) are often used for the generation of a single cell suspension from tissue samples. In this study, flow cytometry was used to examine the effect of chemical agents and enzymes on the expression of cell membrane markers of T lymphocytes from tonsils and peripheral blood. Expression of CD4, CD8, CD25, CD38, L-selectin, CD44, alphaEbeta7 and alpha4beta7 were studied. Incubation of lymphocytes with DTT and EDTA resulted in a decrease of CD38, alphaEbeta7 and alpha4beta7 expression. Incubation with collagenase A and DNAse resulted in a decrease of CD25, L-selectin, alphaEbeta7 and alpha4beta7. The results of this study indicate that a careful interpretation is necessary for phenotypic descriptions of lymphocyte populations obtained by enzymatic isolation techniques.

Focal up-regulation of E-cadherin-catenin complex in inflamed bowel mucosa but reduced expression in ulcer-associated cell lineage.

The E-cadherin-catenin complex is important for the maintenance of epithelial architecture. We studied its expression in Crohn disease, ulcerative colitis, acute ileitis, and controls. Immunohistochemical stainings for E-cadherin, alpha-catenin, beta-catenin and gamma-catenin were performed. E-cadherin messenger RNA (mRNA) was detected using riboprobes. In active inflammation, there was up-regulation of the complex. In particular, epithelium adjacent to ulcers showed increased expression of protein and mRNA, but in ulcer-associated cell lineage, the intensity of staining was weak to negative. In focal inflammation, up-regulation was found in affected areas. Reparative epithelium growing over denuded areas showed weaker expression. Since structural or functional perturbation in any of the molecules of the E-cadherin-catenin complex results in loss of intercellular adhesion, the preexistent epithelium may benefit from up-regulation to try to maintain its normal architecture under inflammatory conditions. Reduced expression in reparative epithelium and ulcer-associated cell lineage could facilitate the motility of these cells.

Influence of the gut and cytokine patterns in spondyloarthropathy.

Clinical and histological studies have previously shown that spondyloarthropathy (SpA) patients can have subclinical gut inflammation. This gut inflammation is related to enterocolitis in Crohn's disease (CD) and may evolve to overt inflammatory bowel disease in a subset of these patients. Moreover, there is an intriguing clinical link between gut inflammation and peripheral joint inflammation. In order to explore immunologically these concepts, recent studies have characterized phenotypically and functionally the inflammatory cells in both the gut and the synovium of SpA patients and have provided a number of new insights. Firstly, they confirm histological and pre-histological alterations of the gut immune system in SpA, which are redundant of CD and which are linked to alterations of the peripheral joints. Secondly, both the acquired and the innate immune system contribute to these alterations, with an important role for both T cells and macrophages and their cytokines. Thirdly, interpretation of these data support the hypothesis that gut and joint inflammation in SpA are induced by the combination of an impaired anti-bacterial host defence and an uncontrolled pro-inflammatory response of the innate immune system. The insights provided by the study of the gut immunology in SpA have contributed to develop new therapeutic strategies, with TNFalpha blockade as prototype.

Gut mucosal T cell lines from ankylosing spondylitis patients are enriched with alphaEbeta7 integrin.

OBJECTIVE: An intriguing link between gut and synovial inflammation exists in patients with spondyloarthropathy (SpA), illustrated by the high frequency of microscopically inflammatory gut lesions observed in these patients. We hypothesise that aberrant homing of mucosal T cells might play a role in the induction/perpetuation of arthritis in SpA. Here, we analyse the expression of the homing molecules alpha4beta7 and alphaEbeta7 on mucosal T cells from patients with ankylosing spondylitis (AS) and controls, in view of the critical role of these receptors in the homing of mucosal lymphocytes. METHODS: Colonic biopsy specimens were obtained from patients with AS (n = 23) and controls (n = 30). Biopsy specimens were immunostained, treated for extraction of intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) or cultured in the presence of IL-2. The expression of the beta7 integrins was investigated. RESULTS: In situ no differences were observed in alphaEbeta7 and alpha4beta7 integrin expression in isolated IEL and LPL, whether determined by flow cytometry or by immunohistochemical staining. In gut mucosal T cell lines, alphaEbeta7 expression was significantly higher in the mucosa of patients with AS compared with controls. Alpha4beta7 was highly expressed on T cells in both groups studied. Mucosal T cells either expressed only the alpha4beta7 integrin or co-expressed the alpha4beta7 and alphaEbeta7 integrins. Almost none of them expressed only the alphaEbeta7 integrin. CONCLUSION: In gut mucosal T cell lines from patients with AS an increased expression of alphaEbeta7 was observed.

History and diagnostic value of antibodies to citrullinated proteins in rheumatoid arthritis.

Rheumatoid arthritis is a chronic inflammatory joint disease characterized by the presence of autoantibodies. The best known autoantibody is the rheumatoid factor. Another group of antibodies directed against citrullinated epitopes is proven to be more specific for rheumatoid arthritis. This review gives an overview of the history of the different anti-citrullinated protein antibody detection methods and their diagnostic and prognostic properties in RA.

Prediction of diagnosis in patients with early arthritis using a combined Kohonen mapping and instance-based evaluation criterion.

Rheumatoid arthritis (RA) and spondyloarthropathy (SpA) are the two most frequent forms of chronic autoimmune arthritis. These diseases lead to important inflammatory symptoms resulting in an important functional impairment. This paper introduces a self-organizing artificial neural network combined with a case-based reasoning evaluation criterion to predict diagnosis in patients with early arthritis. Results show that 47.2% of the sample space can be predicted with an accuracy of 84.0% and attaining a high confidence level. 37.7% of the sample space is classified with an overall accuracy of 65.0%. The remaining group was labeled as "undetermined". A general prediction accuracy of 75.6% is reached, exceeding the performance of other approaches such as a backpropagation neural network and the Quest decision tree program. Furthermore, by using this new method, more specifically case-based reasoning, as a helpful tool to classify patients with early arthritis, the possibility of a confidence measure is given, indicating a degree of "belief" of the system in its results. This is often an important feature when dealing with diagnosis in human patients.

Needle arthroscopy of the knee with synovial biopsy sampling: technical experience in 150 patients.

Needle arthroscopy is an office-based technique allowing direct visualisation of the knee cavity and selective sampling of the synovial membrane. We performed needle arthroscopy in 150 patients with synovitis of the knee (1) to evaluate the diagnostic potential in early arthritis, (2) to perform therapeutic lavage in persistent inflammatory synovitis and (3) to assess the balance between technical feasibility, safety and patient comfort on the one hand, and the relevance of the obtained macro- and microscopic information for diagnosis and research purposes on the other. After disinfection of the leg and local anaesthesia of the skin and joint, a 1.8-2.7 mm needle arthroscope was introduced into the knee. Synovial fluid was aspirated and lavage of the joint cavity was performed to allow macroscopic evaluation of hyperaemia and hypertrophy of the synovial membrane. Biopsies were taken at inflamed sites, followed by another lavage to remove blood and debris. Needle arthroscopy of the knee is a simple and easy to perform technique made particularly attractive by the local anaesthesia and the ambulatory setting. It allows good macroscopic evaluation of synovial inflammation and selective sampling of the synovial membrane. Biopsies are suitable for RNA and DNA extraction, bacterial or lymphocyte culture, and cell isolation. Because samples were sometimes too small for representative histology, we switched from a 1.8 mm to a 2.7 mm biopsy forceps with good results. In nearly all cases the arthroscopy was well tolerated. Moreover, some patients reported relief of symptoms and even improvement of mobility after lavage of the inflamed joint. No major complications were noted. It was concluded that needle arthroscopy of the knee is a simple, safe and well-tolerated technique, with promising perspectives as a diagnostic, scientific and possibly therapeutic tool in rheumatic diseases.

Enhanced costimulation by CD70+ B cells aggravates experimental autoimmune encephalomyelitis in autoimmune mice.

OBJECTIVE: Assess whether CD70+ B cells contribute to EAE. MATERIALS AND METHODS: MOG-specific TCR transgenic mice (2D2) were crossed with mice with constitutive CD70 expression on B cells. The development of EAE and the phenotype of B-T lymphocytes were studied in 2D2xCD70 animals. RESULTS: Spontaneous EAE developed in 20% of 2D2xCD70 and 3% of 2D2 mice. EAE was also more severe in 2D2xCD70 versus 2D2 animals upon MOG immunization. The susceptibility of 2D2xCD70 to EAE was associated with fewer FoxP3+ T cells. CONCLUSIONS: Expression of CD70 by B cells aggravates EAE possibly by reducing the number of regulatory T cells.

Biologics for rare inflammatory diseases: TNF blockade in the SA PHO syndrome.

INTRODUCTION: SAPHO is an invalidating syndrome characterised by Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis. The low prevalence and heterogeneous presentation often leads to a significant diagnostic delay. Here, we provide an up-to-date overview of current insights into the pathogenesis and different treatment options. In addition, we describe the effects of anti-TNF treatment in three refractory cases. CASE REPORTS: Patient A is a 25-year-old female with hidradenitis suppurativa, inflammatory back pain and painful joints. After diagnosis, anti-TNF treatment was started resulting in clinical improvement. Patient B is a 44-year-old woman who presented with acne, palmoplantar pustulosis and anterior chest wall pain. Bone scintigraphy showed increased uptake at the anterior chest wall. Treatment with bisphosphonates resulted in temporary improvement and subsequent treatment with anti-TNF induced long-term clinical improvement. Patient C is a 37-year-old woman with palmoplantar psoriasis, relapsing hidradenitis and inflammatory back pain. MRI revealed osteitis of the pubic bone. Anti-TNF was started for SAPHO syndrome. However, despite a clinical response, our patient discontinued treatment, resulting in rapid deterioration. Anti-TNF treatment was re-introduced followed by clinical improvement. CONCLUSION: These case reports illustrate, consistent with the current literature, that TNF blockers can be considered for treatment of refractory SAPHO syndrome.