Hiroshi Fujinaga

Clinical and Immunomodulatory Effect of Fun-boi, an Herbal Medicine, in Rheumatoid Arthritis.

&NA; Crude preparations of Fun‐boi (Fen‐fan‐ji in Chinese), a traditional antirheumatic herb, have been used safely over millennia. To begin to study the efficacy of Fun‐boi on the disease activity and the peripheral lymphocyte subsets, we performed a 12‐week, open‐label trial of Fun‐boi extract (a decoction of Fun‐boi 10 g/day) in 29 patients with rheumatoid arthritis (RA). Most clinical and immunological variables: swollen joint count, physicians and patients assessment, pain score and IgM rheumatoid factor, showed statistically significant improvement. Seven (24%) of the enrolled patients met the American College of Rheumatology (ACR) criteria for a 20 percent improvement in measures of disease activity (ACR20) and 3 (10%) met those for ACR50. The CD3+CD8+ lymphocytes were increased significantly. Accordingly, the CD4/CD8 ratio was decreased; however, these changes did not show any clear correlation with clinical response. Two patients (7%) experienced some minor transient adverse events. In conclusion, Fun‐boi is safe and showed beneficial effect in some patients for the treatment of the relatively mild RA seen in the patients studied. Further controlled studies are indicated. Clinicians should keep an open mind about possible benefits of these still incompletely studied herbal agents.

A Proteomic Approach for the Diagnosis of ‘Oketsu’ (blood stasis), a Pathophysiologic Concept of Japanese Traditional (Kampo) Medicine

‘Oketsu’ is a pathophysiologic concept in Japanese traditional (Kampo) medicine, primarily denoting blood stasis/stagnant syndrome. Here we have explored plasma protein biomarkers and/or diagnostic algorithms for ‘Oketsu’. Sixteen rheumatoid arthritis (RA) patients were treated with keishibukuryogan (KBG), a representative Kampo medicine for improving ‘Oketsu’. Plasma samples were diagnosed as either having an ‘Oketsu’ (n = 19) or ‘non-Oketsu’ (n = 29) state according to Terasawas ‘Oketsu’ scoring system. Protein profiles were obtained by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and hierarchical clustering and decision tree analyses were performed. KBG treatment for 4 or 12 weeks decreased the ‘Oketsu’ scores significantly. SELDI protein profiles gave 266 protein peaks, whose expression was significantly different between the ‘Oketsu’ and ‘non-Oketsu’ states. Hierarchical clustering gave three major clusters (I, II, III). The majority (68.4%) of ‘Oketsu’ samples were clustered into one cluster as the principal component of cluster I. The remaining ‘Oketsu’ profiles constituted a minor component of cluster II and were all derived from patients cured of the ‘Oketsu’ state at 12 weeks. Construction of the decision tree addressed the possibility of developing a diagnostic algorithm for ‘Oketsu’. A reduction in measurement/pre-processing conditions (from 55 to 16) gave a similar outcome in the clustering and decision tree analyses. The present study suggests that the pathophysiologic concept of Kampo medicine ‘Oketsu’ has a physical basis in terms of the profile of blood proteins. It may be possible to establish a set of objective criteria for diagnosing ‘Oketsu’ using a combination of proteomic and bioinformatics-based classification methods.

Killer-cell inhibitory receptors, CD158a/b, are upregulated by interleukin-2, but not interferon-gamma or interleukin-4.

Although it is now accepted that killer-cell inhibitory receptors (KIRs), which were molecularly cloned in 1995, deliver negative signals to natural killer (NK) cells regarding the recognition of target cells, it is still unclear how the expression of these receptors on lymphocytes is regulated. Therefore, we investigated the regulation of expression of representative KIRs, CD158a and CD158b, by cytokines such as interleukin-2 (IL-2), IL-4 and interferon-gamma (IFN-gamma). Neither IL-4 nor IFN-gamma affected the expression of CD158a/b, but incubation for 48 h with IL-2, which enhances the killer activity of NK cells, upregulated the expression of the KIRs. This upregulation by IL-2 was also observed in CD16-positive cells sorted from total lymphocytes. In contrast, IL-4, which is a down-regulator of IL-2-induced killer responses, did not change the level of CD158a/b expression when added after the IL-2 treatment. These findings suggest that IL-2 plays an important role in the regulation of CD158a/b expression, and might be involved in controlling NK activity via regulating expression of these molecules.

Insights to clinical use of serial determination in titers of cyclic citrullinated peptide autoantibodies.

Anti-cyclic citrullinated peptide (CCP) antibody is a useful marker for the diagnosis and prognosis of rheumatoid arthritis (RA). Recently, clinical significance of follow-up in anti-CCP antibody titer has been pointed out. Thus, we investigated the serial determination in anti-CCP antibodies titer in RA patients. Six patients with RA, who were followed up for longer than 5 years, were assessed in anti-CCP antibodies and radiographs (Larsen score). Anti-CCP antibodies in frozen sera were measured using ELISA. As a result, 6 patients with RA were divided into two groups: one possessed high titers without variation, and the other was without high titers. Joint damage progressed during observation in 2 out of 3 patients with high anti-CCP titers in a retrospective assessment. In contrast, the RA patient, whose anti-CCP titer decreases although it had been high titer at baseline, did not show increase in the Larsen score. These findings suggest that it might be necessary to analyze changes in anti-CCP to predict the prognosis of joint destruction.

Rheumatoid arthritis complicated by mycobacterium tuberculosis are there characteristics predisposing to this association

Several studies have reported that the emergence of mycobacterium tuberculosis (TB) is increasing, and that it may be a critical complication of rheumatoid arthritis (RA). Thus, we assessed the clinical and immune status of RA patients with TB to look for features that might favor infection. Seven RA patients with a history of TB and 62 RA patients without TB were compared in terms of background, RA disease activity, and the concentrations of serum soluble cell surface markers (sCD4, sCD8 and sCD23). There were no differences in RA activity between the two groups. It is noteworthy that the RA patients with TB had not been treated with immunosuppressives. Counts of lymphocytes, but not neutrophils, were significantly less in the RA patients with previous TB than in those without TB. The serum concentration of sCD23, a marker of B cell activation, was significantly higher in the RA with TB group. There was also a nonsignificant but considerable difference in the mean sCD8 concentration between the two groups. These results suggest that B cell and possibly also T cell activation is prominent in the RA patients with a history of TB, and that lymphocyte activation might explain in part the high susceptibility of RA patients to TB.

No Correlation Exists between Disease Activity and the Expression of Killer-Cell Immunoglobulin-Like Receptors in Patients with Rheumatoid Arthritis

Objective. The genes for killer-cell immunoglobulin-like receptors (KIRs) have been cloned and their functions and expression in patients with rheumatoid arthritis (RA) have been partially clarified. However, the correlation between their expression and disease activity has not been analyzed in patients with RA. Thus, we measured KIR expression on lymphocytes in patients with RA, and assessed the correlation between KIR expression and disease activity. Patients and Methods. In the cross-sectional study, 15 patients (9 females and 6 males) who fulfilled the diagnostic criteria for RA were assessed. In the longitudinal study, patients who were followed-up for 3 months were assessed. CD158a/b expression on peripheral blood mononuclear cells (PBMC) of RA patients was analyzed using flow cytometry. Results. No significant correlation between KIR expression and CRP, ESR, or IgM-RF was observed. There was no remarkable change in the expression of KIRs between the baseline and after 3 months. Additionally, in the 5 patients whose expression of KIRs particularly changed, the time-related changes in the expression of KIRs were independent from those of inflammation parameters and IgM-RF. Conclusion. There was no correlation between KIR expression and disease activity; therefore, the clinical use of KIR expression should be limited, while unnatural KIR expression may be involved in the pathogenesis of RA, but not a recruitment of chronic inflammation to induce joint damage.