A case of anti-HMGCR myopathy in a patient with breast cancer and anti-Th/To antibodies.

Statins competitively inhibit the activity of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), which is a key enzyme in cholesterol synthesis. These are effective drugs for the management of cardiovascular disease and are generally well tolerated but several side effects have been reported. Muscular adverse symptoms are various and, rarely, statin exposure may lead to authentic immune-mediated necrotizing myopathy (IMNM), namely anti-HMGCR myopathy. However, cases of IMNM associated with cancer have been described. We discuss herein a case of IMNM in a patient with breast cancer previously exposed to statins and with the presence of anti-Th/To antibodies without clinical correlation.

A case of left foot drop as initial symptom of granulomatosis with polyangiitis: Triggered by COVID-19 disease?

In Granulomatosis with polyangiitis (GPA), involvement of the peripheral nervous system is frequent but its occurrence as an initial presentation is unusual. This case highlights the importance of this occurrence to permit an early diagnosis. Moreover, GPA started after a coronavirus disease 2019 infection and could have been induced by this.

Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis.

INTRODUCTION: In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA. METHODS: Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit. RESULTS: Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3-9 months following the test. CONCLUSIONS: This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.

Association Between Nursing Support Levels and Effectiveness of Golimumab in the Management of Patients with Rheumatologic Diseases.

INTRODUCTION: The main objective of this study was to assess the level of nursing support received by biologic-naïve rheumatological patients treated with golimumab during their first cycle. METHODS: Adult patients (N = 119; aged 46.9 ± 13.4 years (mean ± standard deviation); 49.6% males), with rheumatoid arthritis (N = 40), ankylosing spondylitis (N = 58) or psoriatic arthritis (N = 21), and treated with golimumab (first tumor necrosis factor-α inhibitor) during a first reimbursement cycle were included by 17 Belgian centers. Patients were categorized in three levels of nursing support (intense, medium, or low). They filled in a non-validated and exploratory questionnaire about satisfaction, quality, and helpfulness of information. RESULTS: The nursing support was considered intense, medium, or low for 98 (82.4%), 10 (8.4%), and 11 (9.2%) patients, respectively. All disease activity scores improved versus baseline, and 90% of the patients qualified for treatment prolongation without major differences between nursing level groups. The proportion of patients able to self-inject golimumab was 88, 90, and 73% in the intense, medium, and low support groups, respectively. Satisfaction was high in all three nursing support groups. CONCLUSIONS: This prospective open-label study has confirmed the short-term effectiveness of golimumab in three rheumatological diseases, with most of the patients qualifying for reimbursement renewal. The limited sample size and the fact that the vast majority of patients benefited from an intense nursing support did not allow drawing definite conclusions concerning the impact of the nursing level on the treatment effectiveness and changes in the disease activity. Nurses seem however to play a crucial role in this short-term study but this remains to be confirmed in a longer-term study.

Hidradenitis suppurativa (HS): An unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases.

BACKGROUND: Paradoxical hidradenitis suppurativa (HS) induced by biologic agents (BA) is scarcely reported. OBJECTIVE: We sought to describe the clinical characteristics and outcome of patients developing paradoxical HS under BA. METHODS: This was a multicenter nationwide retrospective study asking physicians to report all cases of HS, confirmed by a dermatologist, occurring during treatment of an inflammatory disease by a BA. RESULTS: We included 25 patients (15 inflammatory rheumatism, 9 Crohn's disease, 1 psoriasis) treated by 5 BA (adalimumab = 12, infliximab = 6, etanercept = 4, rituximab = 2, tocilizumab = 1). Median duration of BA exposure before HS onset was 12 (range 1-120) months. Patients were mostly Hurley stage I (n = 13) or II (n = 11). Simultaneously to HS or within 1 year, 11 patients developed additional inflammatory diseases, including paradoxical reactions (psoriasis = 9, Crohn's disease = 3, alopecia areata = 1, erythema elevatum diutinum = 1). Complete improvement of HS was more frequently obtained after BA discontinuation or switch (n = 6/10, 60%) rather than maintenance (n = 1/14, 7%). Reintroducing the same BA resulted in HS relapse in 3 of 3 patients. LIMITATIONS: Retrospective nature and lack of complete follow-up for some patients are limitations. CONCLUSION: HS is a rare paradoxical adverse effect of BA, but fortuitous association cannot be excluded in some cases. We observed a trend toward better outcome when the BA was discontinued or switched.

Higher expression of TNFα-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy.

BACKGROUND: IL6-related T cell activation and TNFα-dependent cell proliferation are major targets of therapy in the RA synovium. We investigated whether expression of these pathways in RA synovial biopsies is associated with disease activity and response to therapy. METHOD: Correlation and gene set enrichment studies were performed using gene expression profiles from RA synovial biopsies. Immunostaining experiments of GADD45B and PDE4D were performed on independent additional sets of early untreated RA samples, obtained in two different centers by needle-arthroscopy or US-guided biopsies. RESULTS: In 65 RA synovial biopsies, transcripts correlating with disease activity were strongly enriched in TNFα-induced genes. Out of the individual variables used in disease-activity scores, tender joint count, swollen joint count and physician's global assessment, but not CRP or patient's global assessment displayed a similar correlation with the expression of TNFα-dependent genes. In addition, TNFα-induced genes were also significantly enriched in transcripts over-expressed in synovial biopsy samples obtained from poor-responders to methotrexate or tocilizumab, prior to initiation of therapy. GADD45B (induced by TNFα in monocytes) and PDE4D (induced by TNFα in FLS) immunostaining was significantly higher in overall poor-responders to therapy in 46 independent baseline samples obtained from early untreated RA patients prior to initiation of therapy. GADD45B (but not PDE4D) immunostaining was significantly higher in the sub-group of patients with poor-response to methotrexate therapy, and this was confirmed in another population of methotrexate-treated patients. CONCLUSION: Higher expression of TNFα-induced transcripts in early RA synovitis is associated with higher disease activity, and predicts poor response to first-line therapy. That over-expression of TNFα-induced genes predicts poor-response to therapy regardless of the drug administered, indicates that this molecular signature is associated with disease severity, rather than with specific pathways of escape to therapy.

Serum soluble interleukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus.

BACKGROUND: The soluble form of the interleukin 7 receptor (sIL-7R) is produced by fibroblasts after stimulation with proinflammatory cytokines. Increased sIL-7R serum and synovial fluid levels were recently demonstrated in patients with rheumatoid arthritis. OBJECTIVES: To investigate whether sIL-7R production is dysregulated in systemic lupus erythematosus (SLE), and whether this correlates with disease activity. METHODS: Serum and urine sIL-7R concentrations were measured by ELISA, and sIL-7R quantitative PCR (qPCR) studies were performed in peripheral blood mononuclear cells (PBMCs). IL-7R, tumour necrosis factor α (TNFα), IL-1ß and IL-17 immunostainings were performed on kidney sections. RESULTS: sIL-7R concentrations were significantly higher in SLE sera than in controls, and correlated with SLE Disease Activity Index (SLEDAI) scores. Accordingly, serum sIL-7R levels were strongly raised in patients with nephritis. Moreover in patients with lupus nephritis, serum sIL-7R decreased upon treatment. sIL-7R gene expression in PBMCs was similar in patients with lupus nephritis and controls. By contrast, abundant perivascular IL-7R expression was seen in SLE kidney biopsy specimens, which was associated with expression of TNFα in the surrounding tissue. CONCLUSIONS: Our data indicate that sIL-7R is a marker of SLE disease activity, especially nephritis. In contrast to conventional disease activity markers, sIL-7R is not produced by immune cells, but might instead reflect activation of tissue cells in the target organ.

Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis.

INTRODUCTION: To identify markers and mechanisms of resistance to adalimumab therapy, we studied global gene expression profiles in synovial tissue specimens obtained from severe rheumatoid arthritis (RA) patients before and after initiation of treatment. METHODS: Paired synovial biopsies were obtained from the affected knee of 25 DMARD (disease-modifying antirheumatic drug)-resistant RA patients at baseline (T0) and 12 weeks (T12) after initiation of adalimumab therapy. DAS28-CRP (disease activity score using 28 joint counts-C-reactive protein) scores were computed at the same time points, and patients were categorized as good, moderate, or poor responders according to European League Against Rheumatism criteria. Global gene expression profiles were performed in a subset of patients by means of GeneChip Human Genome U133 Plus 2.0 Arrays, and confirmatory immunohistochemistry experiments were performed on the entire cohort. RESULTS: Gene expression studies performed at baseline identified 439 genes associated with poor response to therapy. The majority (n = 411) of these genes were upregulated in poor responders and clustered into two specific pathways: cell division and regulation of immune responses (in particular, cytokines, chemokines, and their receptors). Immunohistochemistry experiments confirmed that high baseline synovial expression of interleukin-7 receptor alpha chain (IL-7R), chemokine (C-X-C motif) ligand 11 (CXCL11), IL-18, IL-18 receptor accessory (IL-18rap), and MKI67 is associated with poor response to adalimumab therapy. In vitro experiments indicated that genes overexpressed in poor responders could be induced in fibroblast-like synoviocytes (FLS) cultures by the addition of tumor necrosis factor-alpha (TNF-alpha) alone, IL-1beta alone, the combination of TNF-alpha and IL-17, and the combination of TNF-alpha and IL-1beta. CONCLUSIONS: Gene expression studies of the RA synovium may be useful in the identification of early markers of response to TNF blockade. Genes significantly overexpressed at baseline in poor responders are induced by several cytokines in FLSs, thereby suggesting a role for these cytokines in the resistance to TNF blockade in RA.

Anti DNA antibodies are not restricted to a specific pattern of fluorescence on HEp2 cells.

BACKGROUND: Antinuclear autoantibody determination relies on an initial screening step using immunofluorescence on HEp2 cells. This may be followed by anti-deoxyribonucleic acid (DNA) determination, if the fluorescence of nuclei is homogeneous. We assessed the validity of a restricted algorithm and compared this to a more comprehensive algorithm that accepted any nuclear pattern as a positive indicator. METHODS: Our retrospective study analyzed routine results for antinuclear antibodies (ANA) and their anti-DNA identification [double stranded nuclear DNA (ds-DNA), membrane associated DNA (mDNA), nucleosomes] for 58 systemic lupus erythematosus (SLE) patients (690 sera). We included 158 patients with systemic or organ-specific autoimmune diseases (888 sera), 44 with viral disease (88 sera), 34 cancer patients (89 sera) and 111 patients with inflammation that served as controls (122 sera) for a total of 1187 samples. RESULTS: 1) Anti DNA antibodies are not associated only with a homogeneous pattern, but can also be seen with a speckled or nucleolar pattern. 2) The observed pattern is typical for a particular patient rather than for a specific pathology. 3) A homogeneous pattern does not necessarily indicate SLE, nor does the presence of circulating anti DNA antibodies. 4) Determination of various specificities of anti DNA antibodies, whatever the immunofluorescent pattern, increases the sensitivity and specificity for SLE. CONCLUSIONS: If diagnosis is based exclusively on a homogenous pattern, preselection would have missed identification of SLE as high levels of anti DNA antibodies were also associated with speckled or nucleolar pattern.