Toshihiro Tono

Predictors of Survival and Causes of Death in Japanese Patients with Systemic Sclerosis

Objective. To clarify the mortality rates, causes of death, and contributing clinical factors in Japanese patients with systemic sclerosis (SSc). Methods. A cohort of 405 patients with SSc, who attended our institution during the period 1973 to 2008, was retrospectively analyzed until the end of 2009. Clinical data were obtained from medical records or autopsy reports. Results. The 405 patients with SSc consisted of 310 (76.5%) survivors, 86 (21.2%) who died, and 9 who were lost to followup. Diffuse cutaneous SSc and involvement of organs other than the gastrointestinal tract were more frequent in patients who died, and were associated with a worse prognosis according to Kaplan-Meier analysis. Female sex, limited cutaneous SSc, anticentromere antibody (ACA), and overlap with Sjögren’s syndrome (SS) were factors favoring a better prognosis, while overlap with myositis contributed to a poor prognosis. The overall 10-year survival rate was 88%. The patients with SSc had a significantly higher mortality than the general population (standardized mortality ratio 2.76), but the patients with ACA or overlapping SS did not. The most common causes of death were unknown ones including sudden death, followed by malignancy and infection. In patients with pulmonary arterial hypertension, sudden death was the most common cause of mortality. Conclusion. The overall mortality rate of patients with SSc was higher than that of the general population, probably because of poor prognostic factors including organ involvement. These factors should be carefully monitored during followup.

An attack of acute neuro-Behcet's disease during the course of chronic progressive neuro-Behcet's disease: report of two cases

A 29-year-old man and a 36-year-old man developed attacks of acute neuro-Behçet’s disease (NB) (right Horner’s syndrome and right hemiplegia and dysarthria, respectively) during the course of chronic progressive NB (acute on chronic). Although both patients recovered from acute NB after treatment with infliximab or corticosteroids, they continued to show manifestations of chronic progressive NB. It is suggested that acute NB and chronic progressive NB are different in their pathogenesis.

Effects of anti-IL-6 receptor antibody on human monocytes

Abstract Objective. To explore the effects of anti-IL-6 receptor antibody, tocilizumab on function of human monocytes. Methods. Monocytes from healthy donors were cultured in the presence of staphylococcal enterotoxin B (SEB) with pharmacologically attainable concentrations of tocilizumab or control IgG. The expression of IL-6 mRNA was determined using quantitative RT-PCR. The expression of CD80 and CD86 and the induction of apoptosis of monocytes were measured using flow cytometry. Results. Tocilizumab promoted apoptosis of SEB-stimulated monocytes. The induction of apoptosis of monocytes by tocilizumab were reversed by addition of IgG, but not IgG F(ab’)2 fragments. Tocilizumab significantly suppressed the expression of CD80, but not that of CD86, on SEB- stimulated monocytes. Finally, tocilizumab significantly suppressed the expression of mRNA for IL-6 of monocytes stimulated with SEB. Conclusions. These results demonstrate that one of the mechanism of action of tocilizumab involves the induction of apoptosis of monocytes, which requires interaction with Fc receptor on monocytes. Moreover, the data also indicate that tocilizumab inhibit IL-6 production of monocytes at mRNA levels.

Transverse myelitis extended to disseminated encephalitis in systemic lupus erythematosus: Histological evidence for vasculitis

A 42-year-old woman was admitted due to systemic lupus erythematosus complicated with glomerulonephritis and pulmonary hypertension. During the treatment for these complications, she presented motor paresis and sensory loss caused by transverse myelitis. In spite of methyl prednisolone pulse therapy, she further developed acute confusional state due to disseminated encephalitis and fell into respiratory arrest. On laboratory examination, elevation of anti-NR2 antibodies in serum as well as in cerebrospinal fluid was noted. Although she recovered from the disseminated encephalitis after extensive treatment with high doses of corticosteroid and intravenous cyclophosphamide, she suddenly died of pulmonary hypertension. Autopsy findings confirmed the presence of liquefaction necrosis in the entire circumference of the whole spinal cord along with intimal hyperplasia and obliteration of the small arteries, accompanied by mononuclear cell infiltration and disruption of internal elastic lamina. It is therefore most likely that our patient developed longitudinal transverse myelitis through spinal cord vasculitis, which extended to brainstem and brain parenchyma, leading to the development of disseminated encephalitis.

Effects of CTLA4-Ig on human monocytes

BackgroundAbatacept, a CTLA4-Ig fusion protein attenuates T cell activation by inhibiting the CD80/86-CD28 costimulatory pathway that is required for the proper T cell activation and thus displays beneficial effects in the treatment of rheumatoid arthritis (RA). Although some studies have disclosed the in vitro effects of this biological agent on the immune-competent cells, the precise mechanisms of action in RA still remain unclear. The current studies were therefore undertaken to explore the effects of abatacept on monocytes in detail.MethodsMonocytes from healthy donors were cultured in the presence of staphylococcal enterotoxin B (SEB) with pharmacologically attainable concentrations of abatacept or control IgG-Fc. The expression of CD80 and CD86 and the induction of apoptosis of monocytes were measured by flow cytometry. The expression of CD80 and CD86 messenger RNA (mRNA) was determined by quantitative RT-PCR.ResultsAbatacept promoted apoptosis of SEB-stimulated monocytes. The induction of apoptosis of monocytes by these biological agents was reversed by the addition of IgG, but not IgG-F(ab′)2 fragments. Furthermore, abatacept significantly suppressed the expression of CD80, but not that of CD86 at protein levels. Finally, abatacept significantly suppressed the expression of mRNA for CD80 of monocytes stimulated with SEB, but not that of CD86.ConclusionsThese results demonstrate that one of the mechanisms of action of abatacept involves the induction of apoptosis of monocytes, which involves interaction with Fc receptor on monocytes. Moreover, the data also demonstrate that abatacept selectively suppresses the expression of CD80 at mRNA levels.

Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid arthritis after 14 weeks of iguratimod add-on to treatment with methotrexate and etanercept

Abstract A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs.

An adult case of human parvovirus B19 infection developed ACPA-positive rheumatoid arthritis

Abstract We report a case of rheumatoid arthritis (RA) developing after parvovirus B19 infection. A 30-year-old Japanese woman, who had no significant medical history admitted for tender erythema in the bilateral upper limbs with progressive polyarthralgia. Serological test showed elevation of serum IgM antibodies for parvovirus B19. Serum anti-cyclic citrullinated peptide antibody (ACPA) and RF were increased at 95.8 U/mL (normal, ≤4.4 U/mL) and 22 IU/mL (normal, ≤15 IU/mL). Radiographs of the hand showed no narrowing of the joint space or bone erosion. Although the erythema of both upper limbs disappeared, polyarthritis persisted. Because C-reactive protein (CRP) and ACPA and RF showed an upward trend, RA was diagnosed together with clinical symptoms. Oral methotrexate was begun at 8 mg/week. Joint pain was alleviated after 1 month, synovitis disappeared after 2 months, and CRP and MMP3 values were negative after 3 months. This case seems to be very rare case which reported a direct relationship between human parvovirus B19 infection and ACPA-positive RA.

Differential influences of Fc gamma receptor blocking on the effects of certolizumab pegol and infliximab on human monocytes

Abstract Objectives: To compare the effects of certolizumab pegol (CZP) and infliximab (IFX) on human monocytes. Methods: Highly purified monocytes from healthy donors were cultured with CZP, IFX, control IgG1, or polyethylene glycol (PEG) at pharmacological attainable concentrations in culture medium with 10% autologous normal human serum (NHS) or with fetal bovine serum (FBS) for 24 h, after which the supernatants were replaced by fresh culture medium containing LPS. After additional 24 h of incubation, the supernatants were assayed for TNF-α and IL-6. In some experiments, the cells were harvested after 1 h of stimulation with LPS for analysis of mRNA for TNF-α by quantitative PCR. Results: Pre-incubation of monocytes with CZP or IFX reduced the production of TNF-α in subsequent cultures stimulated by LPS in a dose-dependent manner. The suppressive effects of IFX on the TNF-α production were significantly diminished, but those of CZP were rather enhanced, in cultures with autologous NHS compared with in cultures with FBS. Addition of IgG, but not IgG F(ab′)2 fragments, significantly inhibited the suppressive effects of IFX on the production of TNF-α and IL-6, whereas either IgG or IgG F(ab′)2 fragments had no significant influences on the suppressive effects of CZP. Furthermore, pre-incubation with CZP or IFX significantly inhibited the expression of mRNA for TNF-α and IL-6 in monocytes compared with PEG or IgG. Conclusion: These results indicate that the mechanism of action of CZP is different from that of IFX. Thus, CZP suppresses the production of proinflammatory cytokines independently of Fc receptors, whereas the suppressive effects of IFX on human monocytes are almost totally dependent on the interaction with Fc receptors.

Acute generalized pustular bacterid concomitant with erythema nodosum, polyarthritis, and Achilles tendinitis

Abstract We report a case of acute generalized pustular bacterid (AGPB) concomitant with erythema nodosum (EN), polyarthritis, and Achilles tendinitis. The patient was admitted with a complaint of fever, widespread plural pustules, erythema, and polyarthralgia. Histopathological examination of the skin lesions demonstrated features of AGBP and EN. Although arthralgia and AGPB can be recognized together, EN and Achilles tendinitis are rare manifestations seen in patients with AGPB. In this case report, we suggest arthralgia, EN, and Achilles tendinitis could coexist with AGPB.