Yusuke Kuwahara

The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab

Objective. SSc is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although the aetiology remains uncertain, many reports have suggested that IL-6 is involved in SSc pathogenesis. Tocilizumab, an anti-IL-6 receptor antibody, is an anti-arthritis medicine that works through the blockade of IL-6 functions. To examine the effect of tocilizumab on SSc, we administered tocilizumab to two SSc patients. Methods. Two dcSSc patients were administered tocilizumab at 8 mg/kg once a month for 6 months. One patient had pulmonary fibrosis assessed by CT and spirometry, and the other had chronic renal failure caused by scleroderma renal crisis. Their skin condition was monitored with a Vesmeter and the modified Rodnan total skin score (mRTSS). Skin biopsies were obtained before and after the tocilizumab treatment to investigate the histological changes. Results. After tocilizumab treatment, both patients showed softening of the skin with reductions of 50.7 and 55.7% in the total z-score of Vesmeter hardness and 51.9 and 23.0% in the mRTSS, respectively. Histological examination showed thinning of the collagen fibre bundles in the dermis. The creatinine clearance in the patient with chronic renal failure improved from 38 to 55 ml/min. However, the fibrotic changes in the lung in the other patient remained unchanged. Conclusions. In the two cases of SSc that we report here, softening of the skin was observed during the treatment with tocilizumab.

Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment

AA amyloidosis is a serious complication of chronic inflammatory and infectious diseases.1 Amyloid fibril deposition causes progressive deterioration in various organs. In October 2007, a 50-year-old woman was admitted to our hospital with severe diarrhoea and weight loss. She had had rheumatoid arthritis (RA) for 12 years. Despite vigorous treatment with prednisolone and disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine, sulfasalazine, auranofin, leflunomide and methotrexate or tacrolimus, her disease remained active. In January 2007, treatment was started with biological drugs. Subcutaneous injection of 25 mg of etanercept twice weekly for 2 months and, subsequently, intravenous injection of 3 mg/kg infliximab for 5 months combined with 20 mg of prednisolone …

Successful treatment of reactive arthritis with a humanized anti–interleukin‐6 receptor antibody, tocilizumab

Reactive arthritis is a disease with the clinical triad of arthritis, urethritis, and conjunctivitis (1). The onset of the disease is often preceded by bacterial infections of Campylobacter, Chlamydia, Salmonella, Shigella, or Yersinia, either in the urogenital or gastrointestinal tract (2,3). HLA–B27 is strongly associated with reactive arthritis, so that this disease is considered as one of the HLA–B27positive spondylarthropathies. Although the pathogenesis of reactive arthritis remains imperfectly understood, bacterial infections trigger systemic immunoreactions, and overproduction of proinflammatory cytokines has been shown to contribute to sterile joint inflammation (1–4). Several kinds of drugs are used for the management of reactive arthritis, including nonsteroidal antiinflammatory drugs (NSAIDs); disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine, methotrexate, and leflunomide; corticosteroids; and immunosuppressive drugs, including azathioprine and cyclosporine, whereas the use of antibiotics remains controversial (1–4). Infliximab, a chimeric anti–tumor necrosis factor (anti-TNF ) antibody, and etanercept, a 75-kd TNF receptor fusion protein, reportedly ameliorated symptoms in patients with reactive arthritis (5–8), as well as other HLA–B27-positive spondylarthropathies (9). However, to our knowledge, there have been no reports regarding the efficacy of the humanized anti–interleukin-6 (IL-6) receptor antibody, tocilizumab (10), for reactive arthritis. Here we report a case of reactive arthritis treated successfully with tocilizumab.

Quantification of hardness, elasticity and viscosity of the skin of patients with systemic sclerosis using a novel sensing device (Vesmeter): a proposal for a new outcome measurement procedure

OBJECTIVES No objective method to measure skin involvement in SSc has been established. We developed a novel method using a computer-linked device to simultaneously quantify physical properties of the skin such as hardness, elasticity and viscosity. METHODS Skin hardness was calculated by measuring the depth of an indenter pressed onto the skin. The Voigt model was used to calculate skin elasticity, viscosity, visco-elastic ratio and relaxation time by analysing the waveform of skin surface behaviour. The results were compared with the modified Rodnan skin score (mRSS) obtained at 17 sites on the bodies of 20 SSc patients and 20 healthy controls. A functional assessment questionnaire was administered to determine how skin hardness represents a patients disability. We also examined intra- and inter-observer variability to determine the reliability of this method. RESULTS The crude hardness obtained with this device correlated well with the standard hardness specified by the American Society for Testing and Materials (ASTM, r = 0.957). A close relationship between hardness and total mRSS was also observed (r = 0.832). Skin elasticity correlated positively, and relaxation time negatively with mRSS. Functional disability correlated more closely with skin hardness (r = 0.643) than with mRSS (r = 0.517). Intra- and inter-observer variabilities were 7.63 and 19.76%, respectively, which were lower than those reported for mRSS. CONCLUSIONS Increases in hardness and elasticity as well as shortening of relaxation time constitute objective characteristics of skin involvement in SSc. The system devised by us proved to be able to assess skin abnormalities of SSc with high reliability.

Preventative Effect of a Flavonoid, Enzymatically Modified Isoquercitrin on Ocular Symptoms of Japanese Cedar Pollinosis

BACKGROUND Flavonoids are nutrients that exert anti-allergic effects. We investigated the preventative effect of enzymatically modified isoquercitrin (EMIQ), a flavonoid, to relieve the symptoms of Japanese cedar pollinosis. METHODS In a parallel-group, double-blind placebo-controlled study design, 24 subjects with Japanese cedar pollinosis took 100mg EMIQ or a placebo for 8 weeks, starting 4 weeks prior to the onset of pollen release. Subjective symptoms, ADL scores and the usage of drugs were recorded daily, and the QOL score was obtained every 4 weeks. Blood sampling was performed before and after the study to measure serum levels of IgE and flavonoids. RESULTS During the entire study period, ocular symptom + medication score for the EMIQ group was significantly lower (p < 0.05) than that of the placebo group. When limited to the period, ocular symptom scores (p < 0.05, weeks 5-6), and ocular congestion scores (p < 0.05, weeks 5-6) for the EMIQ group was significantly lower than that for the placebo group while other scores for the EMIQ group, such as ocular itching scores (p = 0.09, weeks 4-5), lacrimation scores (p = 0.07, weeks 5-6), and ocular congestion scores (p = 0.06, weeks 4-5), all tended to be lower. However no significant differences were found in nasal symptoms between the two groups. Serum concentrations of IgE were not significantly downregulated but the serum concentrations of quercetin and its derivatives were elevated significantly by the intake of EMIQ. CONCLUSIONS Intake of the quercetin glycoside EMIQ proved to be effective for the relief of ocular symptoms caused by Japanese cedar pollinosis.

Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial fibroblast via interference with the Akt signaling pathway

Overgrowth of the synovium plays an important role in the pathogenesis of rheumatoid arthritis (RA). Platelet-derived growth factor (PDGF) is one of the most potent mitogenic factors of synovial cells, and imatinib mesylate (imatinib) is a specific inhibitor of the PDGF receptor tyrosine kinase. The aim of this study was to elucidate the anti-rheumatic activity of imatinib. The in vivo effects of imatinib were assessed by evaluating the sequential manifestation of adjuvant-induced arthritis in rats using paw volume and clinical scores. Imatinib was found to inhibit rat adjuvant-induced arthritis, but the inhibitory effects were incomplete. To confirm the mechanism of anti-rheumatic-activity of imatinib, we assessed the in vitro effects of imatinib on the proliferation of RA synovial fibroblast-like cells (RASFs) using a MTT assay. Intracellular signaling of PDGF was evaluated by Western blot analysis. Platelet-derived growth factor was found to induce a significant proliferation of RASFs, while imatinib inhibited PDGF-induced proliferation of RASF. Imatinib also inhibited PDGF-induced phosphorylation of the PDGF receptor and Akt, whereas constitutive activated extracellular signal-regulated kinase was not inhibited by imatinib. In contrast, imatinib did not inhibit transforming growth factor β- and basic fibroblast growth factor-induced proliferation of RASF. Oral administration of imatinib ameliorated adjuvant-induced arthritis in rats, and it inhibited PDGF-induced RASF proliferation through disruption of the PDGF-R to Akt kinase signaling pathway. Because imatinib cannot inhibit the non-PDGF-dependent proliferation of RASFs, the anti-rheumatic effect of imatinib may be incomplete. The development of inhibitors of RASF proliferation may lead to the successful treatment of RA.

Effect of enzymatically modified isoquercitrin, a flavonoid, on symptoms of Japanese cedar pollinosis: a randomized double-blind placebo-controlled trial.

Background: Flavonoids exert antiallergic and antioxidant effects. We investigated the efficacy of enzymatically modified isoquercitrin (EMIQ), a flavonoid, to relieve symptoms of pollinosis. Methods: In a parallel-group, double-blind placebo-controlled study design, 20 subjects with Japanese cedar pollinosis took two capsules daily of 100 mg EMIQ or a placebo for 8 weeks during the pollen season. Subjective symptoms and activities of daily living (ADL) scores were recorded every day, and the quality of life (QOL) score was obtained every 4 weeks. Blood sampling was performed before and after the study to measure serum cytokines, chemokines, IgE, quercetin and oxidized biomarkers. Results: During the entire study period, total ocular score and ocular itching score for the EMIQ group were significantly lower (p < 0.05) than for the placebo group. When limited to the individual periods, total symptom score for the EMIQ group was significantly lower (p < 0.05, week 4–5) than that for the placebo group while other scores for the EMIQ group, such as total nasal score (p = 0.06, week 4–5), nasal obstruction score (p = 0.08, week 4–5), lacrimation score (p = 0.06, week 5–6), ocular congestion score (p = 0.08, week 4–7) and ADL score (p = 0.08, week 4–7), all tended to be lower. The levels of serum cytokines such as interleukin (IL)-4, IL-5, IL-12, IL-13, interferon-γ, and eotaxin and IgE were not significantly downregulated by the intake of EMIQ but the serum concentrations of oxidized low-density lipoprotein and thymus and activation-regulated chemokine were reduced. Conclusion: Intake of the quercetin glycoside EMIQ was safe and influenced ocular symptoms caused by pollinosis.

Etanercept improved primary biliary cirrhosis associated with rheumatoid arthritis

are surgery, presence of a foreign body, trauma, immunodeficiency, diabetes mellitus, malignancy and sickle cell disease [1]. Only five cases of Peptostreptococcus spp. spondylodiscitis have been reported [4e7] (Table 1). The lack of its recovery in practice may be attributable to improper methods for sample collection, transport and culture (contamination of the sample, exposure to oxygen or desiccation). Most Peptostreptococcus spp. isolates (96%) are susceptible to b-lactam antibiotics [3], although, resistances have been reported against ticarcillin and cefotaxime. Clindamycin and metronidazole are slightly less effective: about 85% of isolates are susceptible [3]. Quinolones, except newer fluoroquinolones as moxifloxacin [8], and aminosides have poor bactericidal activity [3]. When an appropriate antibiotic drug is used, prognosis of spondylodiscitis is the same as with other germs. This case enlights, as recommended by Grados et al. [9], the need for microbial identification and antibiotic susceptibility testing before antibiotic administration. Indeed, bacteria as Peptostreptococcus spp. can be resistant to metronidazole or clindamycin suggested for anaerobic discitis treatment [9].

Epstein-Barr virus associated B-cell lymphoma of brain developing in myelodysplastic syndrome with c-kit mutation (Try-557 stop)

The first case of B‐cell lymphoma of brain in a patient with myelodysplastic syndrome (MDS) was reported. A 68‐year‐old man was admitted because of anemia, fever, and thrombocytopenia and was diagnosed as having MDS (refractory anemia with excess of blasts) on the basis of the findings of bone marrow aspiration and chromosomal analysis. The patient was followed up without chemotherapy, but a brain tumor appeared after 3 years. Histologic and immunohistologic examinations revealed diffuse large B‐cell lymphoma. Mutations of the c‐kit proto‐oncogene (stem cell factor receptor) and the p53 tumor‐suppressor gene were examined in the MDS lesion and malignant lymphoma (ML) by the polymerase chain reaction‐single‐strand conformational polymorphism (PCR‐SSCP) method followed by direct sequencing. The p53 mutation was not found in either MDS or ML, but a nonsense mutation (Try‐557 → stop) in exon 11 of the c‐kit, which might lead to dysfunction of tyrosine kinase activity, was detected in MDS. This is the first report of c‐kit mutation in MDS. Epstein‐Barr virus (EBV) genome was demonstrated in the nucleus of brain ML cells by in situ hybridization with EBV‐encoded RNA‐1 probe. Immunohistochemistry showed that the tumor cells expressed latent infection gene products, including EBV nuclear antigen‐2 and latent membrane protein‐1. This pattern of latent gene expression was Lat III, which is usually found in malignant lymphomas developing in immunocompromised hosts. These findings suggest that a profound pancytopenia in MDS resulted in an immunodeficient condition, after which EBV‐positive B‐cell lymphoma of brain developed. Am. J. Hematol. 65:234–238, 2000.

What kind of durometer is best suited for the assessment of skin disease in systemic sclerosis? comment on the article by Kissin et al

We read with interest the recent article by Kissin et al (1) reporting on the validity of a durometer to objectively measure skin hardness in systemic sclerosis (SSc). The authors demonstrated that durometer-measured skin hardness correlates well with the modified Rodnan skin score (MRSS) and is more reliable than the MRSS. The durometer is a small, easy-to-use, noninvasive instrument that appears promising for everyday clinical use and therapeutic trials. Measurement with a durometer of the hardness of a specimen is based on the extent of the depression produced by the indenter when the resilient force of the specimen becomes equal to the pressure load produced by an inner spring. The durometer was originally designed for use with various industrial materials such as rubber, plastic polymers, and elastomers, so there are many kinds of durometers that have indenters of different shapes and sizes to suit the material. It has not yet been determined which of these is best for assessment of SSc. We therefore used various durometers to measure skin hardness and examined correlations of durometer hardness values with MRSS. The durometers featured 12 different shapes and sizes of indenters consisting of 6 columns and spheres, each with a diameter of 0.5, 1, 2, 4, 6, and 8 mm. A hand-held deep-hole type (GS-719H; Teclock, Nagano, Japan) designed for the measurement of uneven surfaces and relatively soft materials was used. Skin hardness was measured at 17 sites of the body corresponding to those of MRSS in 17 SSc patients (7 diffuse and 10 limited cutaneous types) and 9 healthy control subjects. The mean SD MRSS of the patients was 18.5 11.0. As shown in Figure 1, correlation of durometer hardness with MRSS varied according to the shape and size of the indenter. The most significant correlations were attained with a column-shaped indenter with 2-mm diameter at both dorsal hands and forearms (r 0.76 and 0.73, respectively). The durometer with this indenter demonstrated similar results at other sites, whereas those with other indenters did not always show statistically significant correlations between durometer hardness and MRSS. We discontinued measurements using indenters with a diameter of 0.5 mm and 1 mm because of pain associated with the touch of the instrument. Our findings indicate that the correct selection of a durometer is important. Of the 12 different indenters used in our study, the most suitable is one with a column-shaped indenter with a 2-mm diameter. Positive correlation of durometer hardness with MRSS has also been reported by other investigators (2,3). Durometry, which is objective and easily performed, effectively provides information about skin involvement in SSc and should be considered for use in clinical trials, although it will be necessary to determine the shape and size of the indenter most suitable for the evaluation of skin hardness.