Recent progress in DNA technologies has provided the strategies to regulate the transcription of disease-related genes in vivo using antisense oligodeoxynucleotide (ODN). Transfection of cis-element double-stranded oligodeoxynucleotides (decoy ODNs) has been reported as a new therapeutic tool of anti-gene strategies for gene therapy. In the field of arthritis, decoy ODNs strategies have been significant therapeutic potential. The concept of regulation the disease related gene expression at the level of transcriptional factor may be more therapeutic effects compared with monotherapy in arthritis. Injection of NFκB decoy ODN into the affected joint resulted in marked suppression of joint destruction in CIA models. In vitro studies demonstrated that the inhibitory effect on inflammatory cytokines and matrix metalloproteinase production from stimulated synovial cells derived from rheumatoid arthritis patients. NFκB decoy ODN inhibited induction of osteoclasts and bone resorption ability. Parthenolide is one of the main sesquiterpense lactones responsible for the bioactivities of feverfew and recently reported to inhibit NFκB activation. Parthenolide has ameliorated the severity of joint destruction in experimental animal model. Based upon these findings, NFκB may be one of important therapeutic target for arthritis.

View full abstract

  The progress in molecular targeting therapy includes two tides, namely, small molecule compounds and large molecule biological agents. Although the latter prevails in the field of clinical immunology, the former attracts more and more attention in these few years. Most of molecular targeting small compounds are the inhibitors of tyrosine kinases, including pioneering imatinib which inhibits the receptor for platelet-derived growth factor (PDGF), c-Abl, etc. The therapeutic concentrations of imatinib almost completely abrogated the morphological alteration and proliferation of fibroblastic cells induced by PDGF stimulation in 3-dimensional culture system in vitro. Indeed, imatinib has been shown to be effective in various animal disease models for arthritis, interstitial pneumonia, glomerulonephritis, and pulmonary hypertension. Furthermore, its efficacy in patients with systemic sclerosis has been recently reported from several institutes. Since established treatments had not been found for fibrotic lesion before, imatinib, a dual inhibitor of both transforming growth factor β-, and PDGF-signaling, is likely to be a potent drug against fibrosis. Its efficacy and safety in fibrotic and immune-mediated diseases, such as systemic sclerosis, are currently under investigation throughout the world.

View full abstract

  Treatment of rheumatoid arthritis (RA) has developed dramatically by the appearance of biologics. However the development of a new anti-rheumatic drug is necessary because of its issue on route of administration and expense. Recently, inhibitors targeting tyrosine kinase known as Janus kinase (Jak) has shown prominent effect on RA. Jak family is comprised by Jak1, Jak2, Jak3 and Tyk2 which is necessary for signal transduction for inflammatory cytokines. INCB18424 targeting Jak1/2 and CP690,550 targeting Jak3 has been developed and is now on phase II clinical study for RA. Results from those clinical studies have proven that these inhibitors can be effective as biologics with few side effects. However, it has been reported that inhibitors are less specific than it has been expect and that non-specificity can be important for its effect. Therefore, we think that the mechanism of inhibitors cannot be explained by its inhibition of a single kinase. Herein, we describe IL-10 overproduction by Jak3 and Stat6 deficient dendritic cell. We speculate that this is one possible mechanism of action for CP690,550 although as for its non-specificity we need further investigation to predict not only its effect but also its side effect in a long term administration.

View full abstract

  Fingolimod (FTY720) is the first of a new immunomodulator class : sphingosine 1-phosphate (S1P) receptor modulator. We have found FTY720 by chemical modification of a natural product, myriocin derived from Isaria sinclairii, a kind of vegetative wasp. FTY720 has shown to be highly effective in experimental allograft models and autoimmune disease models. A most striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating effects in these models. It is revealed that the reduction of circulating lymphocytes by FTY720 is due to sequestration of lymphocytes into secondary lymphoid organs and thymus. FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinases. FTY720-P acts as a potent agonist at S1P receptor type 1 (S1P₁), internalizes S1P₁ on lymphocytes, and inhibits the migration of lymphocytes toward S1P. Thus, it is highly likely that immunomodulating effects of FTY720 are caused by inhibition of S1P/S1P₁-dependent lymphocyte egress from secondary lymphoid organs and thymus. Since FTY720 possesses a novel mechanism of action and is reported to be highly effective in multiple sclerosis patients, it is presumed that FTY720 provides a new therapeutic approach for autoimmune diseases including multiple sclerosis.

View full abstract

  Current therapeutic strategies against rheumatoid arthritis (RA) employ increasingly aggressive regimens from an early stage of the disease ; thus, serological markers more specific than IgM-rheumatoid factor (IgM-RF) are desirable. Anti-cyclic citrullinated peptide (anti-CCP) antibody has been reported as a useful and highly specificity marker for the diagnosis of RA. To clarify the diagnostic utility of anti-CCP antibody in early RA, we measured serum concentrations of anti-CCP antibody, IgM-RF, anti-agalactosyl IgG antibody and matrix metalloproteinase (MMP)-3 in 184 polyarthritis patients who showed onset symptoms within the previous 2 years. The diagnostic sensitivity of anti-CCP antibody in early RA was 60.0%, equivalent to IgM-RF (66.3%) and anti-agalactosyl IgG antibody (66.0%). Specificity, positive predictive values and diagnostic accuracy of anti-CCP antibody were the best among the four tested makers. In 38 patients who initially did not meet the ACR criteria for RA, but were diagnosed with RA during the course, the diagnostic sensitivity of anti-CCP antibody was 55.3%. On the other hand, the disease activity score (DAS) 28 of anti-CCP antibody positive and the negative patients was 5.16 and 5.34, respectively. Our data indicated that determination of anti-CCP antibody was useful for early diagnosis of RA.

View full abstract

  A 51-year-old woman was admitted to our hospital because of systemic jaundice, general fatigue in August 24, 2007. She was diagnosed with systemic lupus erythematosus (SLE) as a result of a discoid rash, photosensitivity, lymphocytopenia, elevated serum anti ds-DNA antibody and a positive test for antinuclear antibody. Her laboratory data revealed severe liver dysfunction, suggesting autoimmune hepatitis (AIH). She was also diagnosed with thrombotic thrombocytic purpura (TTP) because of thrombocytopenia, hemolytic anemia, renal dysfunction and decreased ADAM-TS13 activity. The patient was treated by methylprednisolone pulse therapy, fresh frozen plasma infusion and ursodeoxycholic acid. Her symptoms and laboratory data rapidly improved and a liver biopsy was carried out. Interface hepatitis and lymphocyte infiltration were observed in the specimen. A diagnosis of definite AIH was made from her International AIH group score of 20 points. AIH and TTP are rare complications of SLE. The prevalence of the complication of SLE and AIH has been reported as 1.7~2.7%, and that of SLE and TTP as 1~4%. We reported here a rare case of SLE complicated with AIH and TTP.

View full abstract

  We report two elderly male patients with hemophagocytic syndrome (HPS) associated with systemic lupus erythematosus (SLE). They were admitted to the hospital because of general malaise. At admission, they showed fever of unknown origin and hematological abnormalities without typical symptoms for SLE such as arthralgia or malar rash. Chest X-rays, computed tomography and cardiac sonogram demonstrated unilateral pleural and pericardial effusions. Bone marrow aspiration revealed hypocellular marrow with increased macrophages phagocytosing blood cells in the both cases. One patient had positive reactivity for direct Coombs's test and high level of platelet-associated antibody, whose symptoms were ameliorated only by 20 mg per day of prednisolone. The other patient, however, progressive worsened and died regardless of intensive treatment containing methyl-prednisolone pulse therapy. Late-onset lupus (LO-SLE) patients tend to have a more insidious onset of disease, and less frequently show typical symptoms of early-onset SLE such as malar rash. So it seems to be important that clinicians make a fast diagnosis and proper treatment for LO-SLE and associated HPS by careful observation for the latent symptoms and laboratory findings.

View full abstract

  Polymyositis is an uncommon manifestation as a complication of chronic graft-versus-host disease (GVHD). We report a case of a 55 years' old woman diagnosed as polymyositis 2 years after bone marrow transplantation against T-cell lymphoma. Muscle weakness and the elevation of CPK value were compatible with pathognomonic findings of polymyositis. However, the muscle weakness was distributed particularly into distal lower extremities and neck. It is different from that of the typical findings in autoimmune polymyositis. Histological findings showed atrophy and anisocytosis of muscles without invasion of mononuclear cells. This might be a case of GVHD-induced polymyositis occurring symptomatically after substantially progressing under the treatment with immunosuppressive agents to control chronic GVHD after bone marrow transplantation. The treatment with prednisone (1 mg/kg) brought the rapid improvement of muscle weakness and CPK value as well as mouth dryness and cholestatic liver dysfunction like in primary biliary cirrhosis. Moreover, dose up of cyclosporine and addition of mizolibine allowed for the use of lower dose of prednisone. This case suggested that the mononuclear cells invasion into muscles in a chronic GVHD patient could not always be a definitive finding of chronic GVHD-associated polymyositis because of prior use of immunosuppressive agents.

View full abstract

  The patient was a 74-year-old female presenting with abrupt onset of fever and proximal muscle pains. She had been diagnosed with polymyalgia rheumatica (PMR). On physical examination, there was no tenderness or dilatation of the temporal artery and ocular fundi were normal. ¹⁸F-FDG-PET revealed accumulation of FDG in the aorta as well as in the bilateral subclavian arteries, which strongly suggested inflammation of the large blood vessels. Magnetic resonance angiography disclosed stenosis of the bilateral subclavian arteries, which was consistent with angitis. This case was considered to have developed PMR at an old age with positive HLA DR4, and to have a complication large-vessel giant cell arteritis (LV-GCA). Administration of prednisolone at a dose of 20 mg/day promptly relieved the fever and the myalgia as well. It is difficult to diagnose GCA in PMR if no tenderness or dilatation of the temporal artery is present. FDG-PET is considered useful, not only for exploration of tumors, but also for evaluation of inflammation of large vessels.

View full abstract