Takaki Nojima

Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study

Background Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons. Objective To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. Methods 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. Results The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (ΔTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated ΔmTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. Conclusion After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody

OBJECTIVES Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. METHODS Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [(35)S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. RESULTS The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140-positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140-positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like receptors and plays a role in innate immune responses. CONCLUSION The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.

Gamma/delta T cells are the predominant source of interleukin‐17 in affected joints in collagen‐induced arthritis, but not in rheumatoid arthritis

OBJECTIVE Although interleukin-17 (IL-17)-producing gamma/delta T cells were reported to play pathogenic roles in collagen-induced arthritis (CIA), their characteristics remain unknown. The aim of this study was to clarify whether gamma/delta T cells or CD4+ T cells are the predominant IL-17-producing cells, and to determine what stimulates gamma/delta T cells to secret IL-17 in mice with CIA. The involvement of IL-17-producing gamma/delta T cells in SKG mice with autoimmune arthritis and patients with rheumatoid arthritis (RA) was also investigated. METHODS IL-17-producing cells in the affected joints of mice with CIA were counted by intracellular cytokine staining during 6 distinct disease phases, and these cells were stimulated with various combinations of cytokines or specific antigens to determine the signaling requirements. Similar studies were performed using SKG mice with arthritis and patients with RA. RESULTS Gamma/delta T cells were the predominant population in IL-17-producing cells in the swollen joints of mice with CIA, and the absolute numbers of these cells increased in parallel with disease activity. IL-17-producing gamma/delta T cells expressed CC chemokine receptor 6, were maintained by IL-23 but not by type II collagen in vitro, and were induced antigen independently in vivo. Furthermore, IL-17 production by gamma/delta T cells was induced by IL-1beta plus IL-23 independently of T cell receptor. In contrast to what was observed in mice with CIA, IL-17-producing gamma/delta T cells were nearly absent in the affected joints of SKG mice and patients with RA, and Th1 cells were predominant in the joints of patients with RA. CONCLUSION Gamma/delta T cells were antigen independently stimulated by inflammation at affected joints and produced enhanced amounts of IL-17 to exacerbate arthritis in mice with CIA but not in SKG mice with arthritis or patients with RA.

Etanercept-induced anti-Jo-1-antibody-positive polymyositis in a patient with rheumatoid arthritis: a case report and review of the literature

Antitumor necrosis factor (TNF) therapy has been associated with adverse immunologic events including systemic lupus erythematosus. However, the development of polymyositis (PM)/dermatomyositis (DM) associated with anti-TNF therapy is extremely rare. We experienced a case of a 48-year-old female with rheumatoid arthritis (RA) who had anti-Jo-1 antibodies and interstitial lung disease but no previous history of PM/DM and who developed PM soon after the initiation of etanercept (ETN) therapy for RA. The patient recovered upon withdrawal from ETN and corticosteroid (CS) therapies. Only four reports of PM/DM associated with anti-TNF therapy for RA could be found in the literature. The patients described in three of the four reports were positive for anti-Jo-1 antibodies before the initiation of anti-TNF therapy, and in all the cases, recovery occurred after the cessation of anti-TNF-agent administration and CS therapy. These results suggest a relationship between the onset of PM/DM with anti-Jo-1 antibody and anti-TNF therapy for RA.

Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis

Objectives. ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion. Methods. We genotyped HLA-DRB1 alleles for 574 ACPA-positive RA, 185 ACPA-negative RA (including 97 erosive RA) and 1508 healthy donors. We also tested whether HLA-DR SE is associated with RF-negative or ANA-negative RA. Results. ACPA-negative RA with apparent bone erosion was not associated with SE, supporting the idea that ACPA-negative RA is genetically distinct from ACPA-positive RA. We also tested whether these subsets are based on autoantibody-producing activity. In accordance with the ACPA-negative RA subset, the RF-negative RA subset showed a clearly distinct pattern of association with SE from the RF-positive RA. In contrast, ANA-negative as well as ANA-positive RA was similarly associated with SE, suggesting that the subsets distinguished by ACPA are not based simply on differences in autoantibody production. Conclusions. ACPA-negative erosive RA is genetically distinct from ACPA-positive RA.

Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease.

OBJECTIVE To determine the significance of anti-U1 RNP antibodies in the cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD) who have central neuropsychiatric SLE (NPSLE). METHODS The frequency of antinuclear antibodies including anti-U1 RNP antibodies in the sera and CSF of 24 patients with SLE and 4 patients with MCTD, all of whom had neuropsychiatric syndromes, was determined using an RNA immunoprecipitation assay and an enzyme-linked immunosorbent assay. The frequency of anti-U1 RNP antibodies in the CSF of patients with central NPSLE was examined, and the anti-U1 RNP index ([CSF anti-U1 RNP antibodies/serum anti-U1 RNP antibodies]/[CSF IgG/serum IgG]) was compared with CSF interleukin-6 (IL-6) levels and the albumin quotient (Qalb, an indicator of blood-brain barrier damage). CSF and serum antibodies against U1-70K, U1-A, and U1-C, including autoantigenic regions, were examined, and the U1-70K, U1-A, and U1-C indices as well as the anti-U1 RNP index were calculated. RESULTS CSF anti-U1 RNP antibodies with an increased anti-U1 RNP index showed 64.3% sensitivity and 92.9% specificity for central NPSLE. The anti-U1 RNP index did not correlate with CSF IL-6 levels or the Qalb. The anti-U1-70K index was higher than the anti-U1-A and anti-U1-C indices in the CSF of anti-U1 RNP antibody-positive patients with central NPSLE. The major autoantigenic region for CSF anti-U1-70K antibodies appeared to be localized in U1-70K amino acid 141-164 residue within the RNA-binding domain. CONCLUSION The frequency of anti-U1 RNP antibodies in the CSF and the anti-U1 RNP index are useful indicators of central NPSLE in anti-U1 RNP antibody-positive patients. The predominance of anti-U1-70K antibodies in CSF suggests intrathecal anti-U1 RNP antibody production.

Follistatin‐related protein/follistatin‐like 1 evokes an innate immune response via CD14 and toll‐like receptor 4

FRP physically interacts with CD14 by fluorescence‐activated cell sorting (View interaction)

Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical response to infliximab in patients with rheumatoid arthritis: a retrospective clinical study

IntroductionThe induction of antinuclear antibodies (ANAs) or anti-double-stranded (ds) -DNA antibodies (Abs) after infliximab (IFX) therapy in rheumatoid arthritis (RA) is a well-known phenomenon, but the correlation of such Abs with the clinical response to IFX has not yet been determined. The aims of this retrospective observational study were to examine the prevalence of positive ANA and anti-ds-DNA Abs before and after IFX therapy in patients with RA and to investigate whether an increased titer of such Abs is associated with the clinical efficacy of IFX.MethodsOne hundred eleven RA patients who had received IFX were studied. ANA (indirect immunofluorescence with HEp-2 cells) and anti-ds-DNA Abs (Farr assay) results were examined before and after IFX therapy.ResultsThe overall clinical response assessed by EULAR response criteria was as follows: good response in 55%, including remission in 38%; moderate response in 18%; and no response (NOR) in 27%. The positivity of ANA (≥ 1:160) and anti-ds-DNA Abs significantly increased from 25% to 40% (P = 0.03) and from 3% to 26% (P < 0.001) after IFX, respectively. EULAR response differed significantly according to the ANA titer before IFX (P = 0.001), and the efficacy of IFX became worse as the ANA titer before starting IFX increased. Furthermore, the differences in the clinical response of the ANA titer before IFX ≤ 1:80 and ≥ 1:160 were significant (good, moderate, and no response were 66%, 9%, and 25% in ≤ 1:80 group versus 26%, 33%, 41% in ≥ 1:160 group, respectively; P < 0.001). In 13 patients whose ANA had increased after IFX, 10 showed NOR, only one showed a good response, and none reached remission. These clinical responses were significantly different from ANA no-change patients. In 21 patients with positive anti-ds-DNA Abs after IFX, 16 showed NOR, only two showed a good response, and none reached remission.ConclusionsThe present study suggests that the ANA titer before starting IFX predicts the clinical response to IFX. The increased titers of ANA or anti-ds-DNA Abs after IFX may be useful markers of NOR.

Periodic fever and erythema nodosum associated with MDS with trisomy 8: report of two cases and review of the literature.

We report two cases of myelodysplastic syndrome (MDS) with trisomy 8 who had periodic fever and erythema nodosum (EN). A 74-year-old man showed periodic fever and EN. A diagnosis of MDS with trisomy 8 was made, and he was successfully treated with prednisolone (PSL). A 71-year-old man presented with intermittent fever, EN, and recurrent elevation of myogenic enzymes. Despite sustained inflammation, laboratory tests showed macrocytic anemia and thrombocytopenia. Marrow aspiration showed MDS with the chromosomal abnormality trisomy 8. He was successfully treated with PSL without repeated transient fever and elevation of creatine kinase. The results of a literature review of 35 cases of MDS with trisomy 8 and Behçet’s disease-like symptoms, such as EN, oral ulcer and intestinal ulcer, suggest that the disease entity of “trisomy 8 syndrome” may be considered, and that it is an important differential diagnosis of periodic fever and EN.

Systemic lupus erythematosus associated with recurrent lupus enteritis and peritonitis.

We describe the case of a 41-year-old woman with systemic lupus erythematosus (SLE) who suffered from repeated reversible lupus enteritis characterized by marked edematous thickening of the small intestine. Ultrasonography (US) and computed tomography (CT) manifested as an ‘accordion-like appearance’ and a ‘target-like appearance’, respectively. Resolution of gastrointestinal tract wall thickening was observed on follow-up US performed a week after the increase in predinosolone (PSL). We conclude that careful evaluation of sonographic and radiographic findings helps to establish the diagnosis of lupus enteritis.