Treatment resistance of rheumatoid arthritis relates to infection of periodontal pathogenic bacteria: a case-control cross-sectional study.

Recent studies have shown that periodontitis is associated with rheumatoid arthritis (RA) and periodontal bacteria, such as Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) are involved in the pathogenesis of RA via citrullinated proteins. Smoking has also been shown to be involved in the pathogenesis of RA; however, the extent of this involvement is still poorly understood. In addition, RA and polymyalgia rheumatica (PMR) are sometimes difficult to differentiate; however, the relationship between PMR and the factors from smoking and periodontal bacteria is unclear. The aim of this study was to clarify the relationship between periodontal pathogenic bacterial infections and smoking in patients with RA or PMR. This case-control study included 142 patients with untreated RA or PMR. This study evaluated the serum antibody titers against periodontal pathogenic bacterial antigens and an anti-citrullinated peptide antibody (ACPA). In patients with RA, the relationship between antibody titers and disease activity of RA and response after 3 months of treatment was also investigated. Additionally, the effects of smoking were evaluated. Although there was no significant difference in serum antibody titer against periodontal pathogenic bacteria between the ACPA-positive RA group and the ACPA-negative PMR group, we found an association between the elevated antibody titer against Pg and the degree of ACPA value, especially between negative group and high-value positive group (≥ 100 U/mL). The antibody titers against Aa and Pg did not differ depending on disease activity score 28 (DAS28) at baseline; however, patients with high antibody titers had poor RA therapeutic response as judged by DAS28 after 3 months. We could not find any association between smoking and any of these parameters. Periodontal pathogenic bacteria, especially Pg, are associated with elevated ACPA levels. Our findings suggest that Pg and Aa infections interfere with the therapeutic response of RA.

Risk stratification and clinical course of hepatitis B virus reactivation in rheumatoid arthritis patients with resolved infection: final report of a multicenter prospective observational study at Japanese Red Cross Hospital.

BACKGROUND: The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. METHODS: HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. RESULTS: Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive < 2.1 log copies/mL during the observation period. We designed the following scoring system: HBV reactivation risk score = 1 × (age > 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. CONCLUSIONS: Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.

A novel scoring system based on common laboratory tests predicts the efficacy of TNF-inhibitor and IL-6 targeted therapy in patients with rheumatoid arthritis: a retrospective, multicenter observational study.

BACKGROUND: Currently, although several categories of biological disease-modifying antirheumatic drugs (bDMARDs) are available, there are few data informing selection of initial treatment for individual patients with rheumatoid arthritis (RA). Therefore, tumor necrosis factor inhibitor (TNF-i) and tocilizumab (TCZ) are treated as equivalent treatments in the recent disease management recommendations. We focused on two anticytokine therapies, TCZ and TNF-i, and aimed to develop a scoring system that predicts a better treatment for each RA patient before starting an IL-6 or a TNF-i. METHODS: The expression of IL-6 and TNF-α mRNA in peripheral blood from 45 newly diagnosed RA patients was measured by DNA microarrays to evaluate cytokine activation. Next, laboratory indices immediately before commencing treatment and disease activity score improvement ratio after 6 months in 98 patients treated with TCZ or TNF-i were retrospectively analyzed. Some indices correlated with TCZ efficacy were selected and their cutoff values were defined by receiver operating characteristic (ROC) analysis to develop a scoring system to discriminate between individuals more likely to respond to TCZ or TNF-i. The validity of the scoring system was verified in these 98 patients and an additional 228 patients. RESULTS: There was significant inverse correlation between the expression of IL-6 and TNF-α mRNA in newly diagnosed RA patients. The analysis of 98 patients revealed significant correlation between TCZ efficacy and platelet counts, hemoglobin, aspartate aminotransferase, and alanine aminotransferase; in contrast, there was no similar correlation in the TNF-i group. The cutoff values were defined by ROC analysis to develop a scoring system (1 point/item, maximum of 4 points). A good TCZ response was predicted if the score was ≥2; in contrast, TNF-i seemed to be preferable if the score was ≤1. Similar results were obtained in a validation study of an additional 228 patients. If the case scored ≥3, the good responder rates of TCZ/TNF-i were 75.0%/37.9% (p < 0.01) and the non-responder rates were 3.1%/27.6% (p < 0.01), respectively. CONCLUSIONS: The score is easily calculated from common laboratory results. It appears useful for identifying a better treatment at the time of selecting either an IL-6 or a TNF inhibitor.

Adult-onset Still's disease complicated by autoimmune hepatitis: successful treatment with infliximab.

A 17-year-old woman was previously diagnosed with autoimmune hepatitis (AIH) by liver biopsy. Adult-onset Still's disease (AOSD) was subsequently diagnosed on the basis of high fever, arthralgia, erythema, leukocytosis (>80% granulocytes), cervical lymph node swelling, splenomegaly, and hyperferritinemia. Her symptoms and liver dysfunction improved with prednisolone of 60 mg daily and subsequently methotrexate was added. However her symptoms and liver dysfunction relapsed when prednisolone was tapered to 20 mg/day. Therefore infliximab was introduced additionally and her symptoms and liver dysfunction subsided. To our knowledge, this is the first reported case of AOSD with AIH diagnosed by liver biopsy.

A concomitant case of giant cell arteritis and microscopic polyangiitis with hemoperitoneum by rupture of the gastroepiploic artery.

Giant cell arteritis (GCA) mainly involves large-sized arteries, while microscopic polyangiitis (mPA), characterized by pauci-immune necrotizing vasculitis, mainly affects small-sized vessels. We report a very rare concomitant case of GCA diagnosed by temporal artery biopsy and mPA with a high titer of myeloperoxidase antineutrophil cytoplasmic antibody, exacerbation of interstitial pneumonia, and suspected rapidly progressive glomerulonephritis. The patient died by sudden rupture of the gastroepiploic artery (medium-sized vessel), which may have been triggered by GCA and/or mPA.

Etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis patients intolerant to methotrexate.

Although etanercept (ETN) is effective when used in monotherapy for the treatment of rheumatoid arthritis (RA), ETN/methotrexate (MTX) combination therapy is more efficacious. However, some patients show MTX intolerance; these patients may develop adverse events (AEs) or have risk factors for AEs. There is limited published information regarding the efficacy of combination therapy involving ETN and disease-modifying antirheumatic drugs other than MTX. Therefore, we evaluated the effects of combination therapy with ETN and salazosulfapyridine (SASP) and/or bucillamine (Bc), a D: -penicillamine analogue, in MTX-intolerant RA patients. Indices of RA activity, including disease activity score in 28 joints (DAS28), were retrospectively analyzed over a 48-week period in 66 patients treated with ETN. Treatment efficacy was compared in the following 4 major treatment groups: ETN monotherapy, ETN + MTX, ETN + SASP, and ETN + SASP + Bc. Although intergroup differences in the percent change of DAS were not statistically significant, ETN + SASP + Bc seemed to be more effective than ETN monotherapy, and the efficacy of ETN + SASP + Bc was comparable to that of ETN + MTX according to the European League Against Rheumatism (EULAR) improvement ratings. These results suggest that ETN + SASP + Bc combination therapy may be a viable option for RA treatment in patients in whom MTX cannot be used.

Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism.

Interleukins (IL) 1 and 6 are important cytokines that function via the activation, respectively, of the transcription factors NF-kappaB and STAT3. We have observed that a specific type of kappa B DNA sequence motif supports both NF-kappaB p65 homodimer binding and cooperativity with non-tyrosine-phosphorylated STAT3. This activity, in contrast to that mediated by kappaB DNA motifs that do not efficiently bind p65 homodimers, is shown to be uniquely dependent upon signal transduction through the carboxyl terminus of TRAF6. Furthermore, STAT3 and p65 are shown to physically interact, in vivo, and this interaction appears to inhibit the function of "classical" STAT3 GAS-like binding sites. The distinct p50 form of NF-kappaB is also shown to interact with STAT3. However, in contrast to p65, p50 cooperates with STAT3 bound to GAS sites. These data argue for a novel transcription factor cross-talk mechanism that may help resolve inconsistencies previously reported regarding the mechanism of IL-1 inhibition of IL-6 activity during the acute-phase response.

Characterization of a cascade of protein interactions initiated at the IL-1 receptor.

Prior studies have identified molecules involved in IL-1 signaling that transmit the extracellular stimulus to downstream kinase molecules causing altered transcriptional activity. Many of these investigations have relied heavily on ligand induced protein-protein interactions detected by immuno-coprecipitation to map the cascade of events from receptor binding to activation of downstream signaling intermediates. Direct protein interactions have not been commonly reported. An in vitro study was undertaken to better define the direct protein-protein interactions involved in IL-1 signaling. Results indicate that IRAK2 is capable of direct association with either IL-1R(I) or IL-1R(AcP). IRAK2 is also capable of associating directly with MyD88 by distinct regions. Finally, IRAK2 interactions with TRAF6 were mapped and demonstrate differences from more proximal signaling intermediates. A model is presented that reflects the specific molecular interactions responsible for recruiting signaling intermediates to the IL-1 receptor cytoplasmic domains.