Tocilizumab is a highly effective therapeutic agent for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Furthermore, a large amount of case study data reveals that tocilizumab can be an effective therapy for not only rheumatoid arthritis but also for other mostly rare inflammatory rheumatic diseases. By blocking the interleukin-6 pathway tocilizumab can be a useful therapeutic alternative when conventional treatment fails. It is successful in treating diseases such as the adult-onset Still's disease, amyloidosis, giant cell arteritis, multiple myeloma, polymyalgia rheumatica, relapsing polychondritis, remitting seronegative symmetrical synovitis with pitting edema-syndrome, systemic lupus erythematosus, systemic sclerosis, and Takayasu arteritis. Studies underway are now recruiting patients to acquire further data on treating patients with non-rheumatic arthritis, inflammatory diseases. This review focuses on tocilizumab as a promising agent for treating rare and orphan diseases in rheumatology for which no satisfactory treatment is yet available.

A traditional infectious disease vaccine is a preparation of live attenuated, inactivated or killed pathogen that stimulates immunity. Vaccine immunologic adjuvants are compounds incorporated into vaccines to enhance immunogenicity. Adjuvants have recently been implicated in the new syndrome named ASIA autoimmune/inflammatory syndrome induced by adjuvants. The objective describes the frequencies of post-vaccination clinical syndrome induced by adjuvants. We performed a cross-sectional study; adverse event following immunization was defined as any untoward medical occurrence that follows immunization 54 days prior to the event. Data on vaccinations and other risk factors were obtained from daily epidemiologic surveillance. Descriptive statistics were done using means and standard deviation, and odds ratio adjusted for potential confounding variables was calculated with SPSS 17 software. Forty-three out of 120 patients with moderate or severe manifestations following immunization were hospitalized from 2008 to 2011. All patients fulfilled at least 2 major and 1 minor criteria suggested by Shoenfeld and Agmon-Levin for ASIA diagnosis. The most frequent clinical findings were pyrexia 68 %, arthralgias 47 %, cutaneous disorders 33 %, muscle weakness 16 % and myalgias 14 %. Three patients had diagnosis of Guillain-Barre syndrome, one patient had Adult-Still's disease 3 days after vaccination. A total of 76 % of the events occurred in the first 3 days post-vaccination. Two patients with previous autoimmune disease showed severe adverse reactions with the reactivation of their illness. Minor local reactions were present in 49 % of patients. Vaccines containing adjuvants may be associated with an increased risk of autoimmune/inflammatory adverse events following immunization.

Adult onset Still's disease (ASD) is a systemic inflammatory disorder of unknown etiology. ASD is characterized by fever with unknown etiology, rash, arthritis, and involvement of several organ systems. FMF and TRAPS are two important autoinflammatory diseases which characterized with recurrent inflammatory attacks. We aimed in this study to investigate the MEFV gene and TNFRSF1A gene variations in ASD. Twenty consecutive Turkish ASD patients (14 female and 6 male; mean age 38.45 ± 14; mean disease duration 3.3 ± 2.3; mean age of the disease onset 35.1 ± 14.4) and 103 healthy controls of Turkish origin were analyzed. All ASD patients were genotyped for the 4 MEFV mutations (M694V, E148Q, V726A, M680I) and TNFRSF1A gene exon 2-3 and exon 4-5 by using sequence analysis. The healthy controls are genotyped using PCR-RFLP method for intron 4 variation. The results of MEFV gene mutations screening show an increase in the MEFV mutation rate in ASD group, but it was not significantly different (p = 0.442, OR 1.64, 95 % CI 0.409-6.589). T-C polymorphism (rs1800692) was the only variation in the intron 4 of TNFRSF1A gene that we observed at the ASD patients. The frequency of TT genotype was 15 %, TC: 45 %, and CC: 40 % in ASD patients and the frequencies were 22, 41, and 37 % in healthy controls, respectively. When we analyzed the allele difference between both groups, there was no difference (p = 0.54, OR 1.24, 0.619-2.496-2.654). The variations in MEFV may have role in ASD pathogenesis. Our findings suggest that there is no significant association between ASD and TNFRSF1A variations.

Adult-onset Still's disease (AOSD) is a rare chronic inflammatory disorder presenting with prolonged fever and polyarthritis.Retrospective study of patients with AOSD, seen between 1992 and 2009 at a large tertiary care hospital.Twenty-nine patients (18 female) with median age at onset of 28 (17-58) years were seen. The clinical features included fever in 29, inflammatory polyarthritis in 26, sore throat in eight and typical rash in 13. Lymphadenopathy was present in 15, hepatomegaly in 15, splenomegaly in 13 and serositis in five patients. Anemia was present in 22, neutrophilic leukocytosis in 28 and thrombocytosis in 13 patients. Acute phase reactants were elevated in all. Fifteen patients had transaminitis. Low titer antinuclear antibodies were present in 6/28 patients. On median follow-up (25 patients) of 23.7 months (range: 3-84) one patient had self-limited or monocyclic pattern, eight had polycyclic and 16 had chronic articular pattern. All patients received non-steroidal anti-inflammatory drugs and 25 received methotrexate and/or prednisolone. During the course 14 patients had remission and of these six were in remission on drugs at last follow-up. One patient received tociliziumab and was in clinical remission. One patient developed macrophage activation syndrome and one had atlanto-axial dislocation. Three patients developed tuberculosis and two died of infection associated with immunosuppression.AOSD is an uncommon disorder with 1-2 patients seen at a large tertiary care rheumatology unit. Overall AOSD has a fair outcome with significant morbidity and most needing long-term therapy with steroids and methotrexate.

Adult-onset Still's disease (AOSD) is a rare inflammatory condition characterized by spiking quotidian fever, rash, chronic arthralgia, leukocytosis, and occasional pulmonary involvement such as pleural effusion and transient pulmonary infiltrates. Pulmonary arterial hypertension (PAH) is a rare pulmonary complication of AOSD, and we are aware of only 5 cases reported in the literature. We report the case of a 27-year-old woman of Middle Eastern descent, with a 7-year history of AOSD, who developed severe pulmonary arterial hypertension (PAH). After unsuccessful exposure to various immunosuppressive regimens, shortly following the initiation of anakinra, an interleukin-1 (IL-1) receptor antagonist, her disease became quiescent and the PAH resolved. With this case report, we hope to show that anakinra, either by virtue of controlling the overall inflammation in AOSD, or by direct effect on the pulmonary microangiopathy, can improve severe PAH.

The proinflammatory cytokine interleukin (IL)-18 was originally discovered as an interferon-γ-inducing factor in 1995. IL-18 is known to play an important role in Th1/Tc1 polarization and promoting the production of Th2 cytokines (e.g., IL-4, IL-5, IL-9, and IL-13) by T cells, NK cells, basophils, and mast cells. IL-18 can act as a cofactor for Th2 cell development and IgE production, and also plays an important role in the differentiation of Th17 cells. IL-18 is a key player in the pathogenesis of inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, adult-onset Still's disease, Sjögren's syndrome, and inflammatory bowel diseases. Furthermore, many lines of evidence suggest that IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases, including bronchial asthma and chronic obstructive pulmonary disease. Here, we review the pathological roles of IL-18 in pulmonary inflammatory diseases.

Germinal center kinase-like kinase (GLK, also termed MAP4K3), a member of the MAP4K family, may regulate gene transcription, apoptosis and immune inflammation in response to extracellular signals. The enhanced expression of GLK has been shown to correspond with disease severity in patients with systemic lupus erythematosus. We investigated the role of GLK in the pathogenesis of adult-onset Still's disease, which shares some similar clinical characteristics with systemic lupus erythematosus.The frequencies of circulating GLK-expressing T-cells in 24 patients with active adult-onset Still's disease and 12 healthy controls were determined by flow cytometry analysis. The expression levels of GLK proteins and transcripts were evaluated in peripheral blood mononuclear cells by immunoblotting and quantitative PCR. Serum levels of T helper (Th)17-related cytokines, including IL-1β, IL-6, IL-17 and TNF-α, were measured by ELISA.Significantly higher median frequencies of circulating GLK-expressing T-cells were observed in patients with adult-onset Still's disease (31.85%) than in healthy volunteers (8.93%, P <0.001). The relative expression levels of GLK proteins and transcripts were also significantly higher in patients with adult-onset Still's disease (median, 1.74 and 2.35, respectively) compared with those in healthy controls (0.66 and 0.92, respectively, both P <0.001). The disease activity scores were positively correlated with the frequencies of circulating GLK-expressing T-cells (r = 0.599, P <0.005) and the levels of GLK proteins (r = 0.435, P <0.05) or GLK transcripts (r = 0.452, P <0.05) in patients with adult-onset Still's disease. Among the examined Th17-related cytokines, elevated levels of serum IL-6 and IL-17 were positively correlated with the frequencies of circulating GLK-expressing T-cells and the levels of GLK proteins as well as transcripts in patients with adult-onset Still's disease. GLK expression levels decreased significantly after effective therapy in these patients.Elevated expression levels of GLK and their positive correlation with disease activity in patients with adult-onset Still's disease indicate that GLK may be involved in the pathogenesis and act as a novel activity biomarker of this disease.

To investigate natural killer (NK) cell proportions, NK cell cytotoxicity, and interleukin 18 (IL-18) expression, in patients with adult-onset Still's disease (AOSD).Forty-five patients with AOSD (active = 22, inactive = 23) and 32 healthy controls were included. The proportions of NK cells among peripheral blood mononuclear cells were assessed by flow cytometry. IL-18 and IL-18-binding protein (IL-18BP) concentrations were measured by ELISA. Twenty-four patients with AOSD and 18 controls were examined for cytotoxic activity of NK cells by co-incubating NK cells with NK-sensitive K562 cells. The association of NK cell function with clinical and laboratory measures was investigated.The proportions of NK cells were significantly lower in patients with active AOSD than in patients with inactive disease and controls. NK cell cytotoxic function was significantly lower in patients with AOSD than in controls. NK cell proportions and cytotoxic functions were reexamined in 11 and 6 patients, respectively, after treatment. Low NK cell proportion and cytotoxic dysfunction were improved with clinical improvements of the patients. IL-18 and IL-18BP levels were much higher in patients with active AOSD than in controls. NK cell cytotoxic functions were consistently low and IL-18 and IL-18BP levels were constantly high in patients with AOSD, regardless of disease activity.Low NK cell proportion, defective cytotoxic function, and elevated IL-18 levels may be significant features of AOSD. After resolution of the acute phase, low NK cell proportion was recovered and NK cell cytolytic function was restored along with clinical improvement. These findings possibly contribute to immunologic abnormalities in AOSD.