A disease, which repeats inflammations but is not based on infections or autoimmunity, was recently defined as autoinflammatory diseases. The autoinflammatory diseases are a new and expanding classification of inflammatory diseases characterized by recurrent episodes of systemic inflammation in the absence of pathogens, autoantibodies or antigen specific T cells. This disease is developed by the abnormality of molecules which regulate inflammation, innate immunity and apoptosis, and patients have been suffered with treatment by the difficulty of making a diagnosis. However, a diagnosis is comparatively easy by their presenting the characteristic clinical observation. In addition, genetic analysis can put the diagnosis on a firm basis. Giving that therapies for individual disorder of autoinflammatory diseases are different, we always put these disorders in mind when we saw patients who have unknown persistent inflammation.

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  The latest decade, our understanding of pattern-recognizing receptors involved in innate immune system has been accumulated. One class of the pattern recognizing receptors, the toll-like receptors (TLRs) are well known to detect extracellular pathogens on the cell surface membrane. On the other hand, recently discovered the nucleotide-binding oligomerization domain proteins (NODs) are involved in recognizing intracellular pathogens. Since Nod2, one of the NODs, mutations were found to associate with susceptibility of Crohn's disease, the NODs have been highlighted. For example, cryopyrin mutations have been reported to associate with Familial cold urticaria (FCU)/Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Neonatal onset multisystem inflammatory disease (NOMID)/Chronic infantile neurologic cutaneous and articular syndrome (CINCA). Here, we summarize the discovery of the NODs and related molecules, and also discuss the function of the NODs and molecular mechanisms of the autoinflammatory diseases.

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  Familial Mediterranean fever (FMF) is an autosomal recessive disease which predominantly affects certain ethnic groups mainly Sephardic Jews, Turks, Arabs and Armenians. FMF has been rarely reported in Japan. Characteristic symptoms include self-limited recurrent attacks of fever with serositis such as peritonitis, pleuritis, and arthritis. The most serious complications of FMF are secondary AA amyloidosis and subsequent chronic renal failure. FMF is caused by mutations in MEFV gene which encodes a protein called pyrin. Pyrin regulates processing of IL-1β, NF-κB activation and apoptosis. Dysregulated function of pyrin results in excessive production of proinflammatory cytokine thereby evoking inflammatory attacks. The mainstay of treatment is colchicine which is effective for both relieving symptoms and preventing secondary amyloidosis.

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  Hyper IgD and periodic fever syndrome (HIDS; OMIM 260920) is one of the hereditary autoinflammatory syndromes characterized by recurrent episodes of fever and inflammation.. HIDS is an autosomal recessive disorder characterized by recurrent fever attacks in early childhood. HIDS caused by mevalonate kinase (MK) mutations, also that is the gene of mevalonic aciduria (OMIM 251170). During febrile episodes, urinary mevalonate concentrations were found to be significantly elevated in patients. Diagnosis of HIDS was retrieving gene or measurement of the enzyme activity in peripheral blood lymphocyte in general. This of HIDS is an activity decline of MK, and a complete deficiency of MK becomes a mevalonic aciduria with a nervous symptom. The relation between the fever and inflammation of mevalonate or isoprenoid products are uncertain. The therapy attempt with statins, which is inhibited the next enzyme after HMG-CoA reductase, or inhibit the proinflammatory cytokines.

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  TNF receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited disease characterized by prolonged episodes of periodic fever and localized inflammation. The hypothetical pathogenesis of TRAPS is defective TNF receptor 1 (TNFRSF1A) shedding from cell membranes in response to a stimulus including TNFα. This mechanism has recently been shown to account for a minor population of TRAPS patients and other mechanisms are reported to explain the disease, such as resistance to apoptosis, TNFRSF1A internalization, or TNFRSF1A misfolding and aggregation, leading to NF-κB activation and apoptosis.
  Until now 15 TRAPS patients from 5 pedigree including 5 different mutations (C30R, C30Y, T61I, C70S, C70G) had been reported in Japan. There were many sporadic cases of TRAPS without TNFRSF1A mutation in our epidemiological study.
  In this issue, we described the clinical characterization, pathogenesis, diagnostic criteria, and treatment of TRAPS according to our case and literature.

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  PFAPA is non-hereditary syndrome characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis and cervical adenitis. It manifests usually in early childhood, especially before 5 years of age, and last for several years. Its etiology is unknown, but some recent reports suggest a dysregulation of the immune response with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response both during and between febrile attacks. The diagnosis is clinical and it is important to exclude other entities of similar presentation with periodic fever and orofacial manifestations. The findings of laboratory are unspecified and show only nonspecific acute inflammatory response. Several treatments have been performed but with various results. Most effective therapy for a fast resolution of the symptoms is one or two doses of oral prednisone, but its efficacy is not permanent. Effectiveness of cimetidine and tonsillectomy in PFAPA is not clear as yet. PFAPA is a benign syndrome and the prognosis is better than other autoinflammatory syndromes, because PFAPA patients grow normally and symptoms diminish within a few years.

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  CINCA syndrome is an autoinflammatory syndrome characterized by neonatal onset of urticarial rash, central nervous system lesions and arthropathy. Laboratory findings show leucocytosis, anemia, elevation of CRP levels and acceleration of ESR.
  The syndrome is associated with CIAS1 gene and its encoding protein cryopyrin. The CIAS1 gene is expressed in monocytes, polymorphonuclear cells and chondrocytes. Mutations of cyropyrin lead to the persistent production of IL-1β and activation of NF-κB, followed by excessive inflammtory reactions. In spite of aggressive therapies, the inflammation persists and the lesions are progressive. Recently, there have been reports of clinical improvement using human recombinant IL-1 receptor antagonsist anakinra in the patients with CINCA syndrome and its related diseases, Muckele-Wells syndrome and familial cold-autoinflammatory syndrome, suggesting that IL-1β plays an important role in the pathogensis of the inflammation associated with the CIAS1 gene mutations. No serious adverse reaction of anakinra has not been reported. Following the diagnosis of CINCA syndrome, anakinra therapy should be started as the first line of therapy before irreversible disabilities develop. Treatment with anakinra has just begun, therefore, it is necessary to carry out further investigations concerning the adverse effects of anakinra and long-term prognosis for CINCA syndrome treated with anakinra.

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  Muckle-Wells syndrome (MWS), as well as familial cold autoinflammatory syndrome (FCAS) and chronic infantile neurological cutaneous and articular syndrome (CINCA), arises from a missense mutation in the CIAS1 gene. Current progress of biology revealed that NALP3, a protein coded by the CIAS1 and expressed in monocytes, recognizes some bacterial products or harmful metabolites invaded in the cytoplasm, and forms inflammasome with other molecules. As a result, caspase-1 is activated leading to cleavage of pro-IL-1β and extracellular release of IL-1β. NALP3 of patients with MWS can be spontaneously activated without obvious stimulation, which causes recurrent attacks of inflammatory symptoms characterized by fever, urticarial rash, conjunctivitis and arthritis, and some patients develop amyloidosis. In addition, sensorineural hearing disturbance progresses gradually. Recently, significant efficacy of anakinra, a recombinant IL-1 receptor antagonist, has been demonstrated in treatment of MWS. So far, only a few cases have been reported from Japan, however an accurate diagnosis has to be established for the latent cases who have not received optimum treatment before occurrence of irreversible deafness or renal failure.

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  Sarcoidosis is a systemic inflammatory disease clinically characterized by swelling of bilateral hilar lymph nodes and histologically defined by non-caseating epithelioid cell granulomas. Among child cases, a special subtype, called the early-onset sarcoidosis, is known to appear in children younger than 4 years of age and to be characterized by a distinct triad of skin, joint and eye disorders without pulmonary involvement. On the other hand, autosomal dominantly-transmitted disease with a characteristic features similar to those of early-onset sarcoidosis has been reported as Blau syndrome. By a linkage analysis, the responsible gene for Blau syndrome has been mapped close to the IBD (Inflammatory Bowel Disease) 1 locus. After CARD15 (NOD2), originally identified as the susceptibility gene for Crohn's disease, was also proved to be responsible for Blau syndrome, the same gene mutations have been found in sporadic early-onset sarcoidosis cases. Nod2 recognizes a signal from bacterial cell wall component in the cytoplasm of monocytic cells to activate NF-κB, and thus can work as an intracellular sensor of bacteria. While the loss-of-function mutations in its LRR domain are associated with Crohn's disease, Blau syndrome and early-onset sarcoidosis are autoinflammatory diseases that are caused by the gain-of-function mutations in its NOD domain.

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  We herein report the successful use of rituximab in a 55-year-old woman with refractory PR3-ANCA-associated Wegener's granulomatosis. She responded to treatments with high dose methylprednisolone (mPSL), oral and intravenous cyclophosphamide, intravenous gammaglobulin, immunoabsorption, oral prednisolone (PSL), and oral ciclosporin, although she frequently relapsed with various symptoms, such as perforation of the small intestine, scleritis, orbital granuloma, complete AV block, multiple lung nodules, cerebellar infarction, and pharyngeal granuloma with a high level of PR3-ANCA. During her latest relapse, she was given high dose mPSL and 2 infusions of 600 mg (375 mg/m²) of anti-CD20 monoclonal antibody rituximab with an interval of 4 weeks, followed by a tapering of the administered PSL. The patient's PR3-ANCA levels normalized within 2 months, but at 6 months after the beginning of the administration of rituximab, the PR3-ANCA level gradually increased without any clinical symptoms. Therefore, two more infusions of rituximab were again administered and thereafter the PR3-ANCA level finally normalized. At present, at 14 months after the initial rituximab treatment, the patient's remission continues to be maintained. The successful treatment of this patient by rituximab therefore suggests that it is an effective and new therapeutic approach for the treatment of refractory Wegener's granulomatosis.

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  A 67-year-old female noticed dyspnea on exertion associated with the development of erythema in the eyelids and the bilateral fingers, and was admitted to our hospital on July 21, 2004. Proximal muscle weakness in the limbs, heliotrope rash, and Gottron's sign were observed, but the CK level was normal (194 U/l). All autoantibodies except for rheumatoid factor were negative. Hypoxemia and interstitial pneumonia on chest CT images were observed. Based on these findings, a diagnosis of advanced interstitial pneumonia associated with dermatomyositis was made. Combination immunosuppressive therapy was initiated with corticosteroid pulse therapy and cyclosporin-A (Cy-A), resulting in marked improvement. The Cy-A trough concentration was markedly high (456.4 ng/ml). When cytomegalovirus infection developed, the dose of Cy-A was reduced. Although the blood trough concentration of Cy-A was maintained at an adequately high level, the patient died of recurrence of rapidly progressive interstitial pneumonia. Careful observation is required when the dose of Cy-A is reduced for a patient with interstitial pneumonia associated with dermatomyositis. Furthermore, it is suggested that the trough concentration level of Cy-A is not always a useful parameter.

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