Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: A Japanese multicentre investigational study (ORIGAMI study).

OBJECTIVES: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan. METHODS: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry. RESULTS: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively. CONCLUSIONS: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting.

Prevalence of anti-cyclic citrullinated peptide antibodies in patients with spondyloarthritis: A retrospective study.

OBJECTIVES: Anti-cyclic citrullinated peptide (CCP) antibodies are frequently detected in the sera of patients with rheumatoid arthritis (RA). However, recent studies have revealed a potentially high prevalence rate of these antibodies in patients with other rheumatic disorders, causing confusion while diagnosing RA. Therefore, this study aimed to evaluate the positive rate of anti-CCP antibodies in other chronic arthritis diseases focusing on patients with spondyloarthritis (SpA). METHODS: A total of 109 patients who were diagnosed with SpA at Yukioka Hospital from 1993 to 2018 were included in this retrospective analysis, including patients with ankylosing spondylitis (AS); psoriatic arthritis (PsA); synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO); undifferentiated spondyloarthritis (uSpA); reactive arthritis (ReA); and inflammatory bowel disease-associated SpA (IBD). RESULTS: Overall, 15.3% (16/109) of patients with SpA were positive for anti-CCP antibodies, including 2.3% (1/43) in AS, 23.1% (3/13) in SAPHO, 35.0% (7/20) in PsA, 14.8% (4/27) in uSpA, 0% (0/3) in ReA, and 33.3% (1/3) in IBD. CONCLUSION: PsA patients have a significantly higher prevalence rate of positive anti-CCP antibodies among SpA patients, and the positive rates in SAPHO and uSpA were also high. These findings provide insight into the heterogeneity of SpA with relevance for RA differential diagnosis.

Psychological state is related to the remission of the Boolean-based definition of patient global assessment in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate whether the psychological state is related to the Boolean-based definition of patient global assessment (PGA) remission in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who met the criteria of swollen joint count (SJC) ≤ 1, tender joint count (TJC) ≤ 1 and C-reactive protein (CRP) ≤ 1 were divided into two groups, PGA remission group (PGA ≤ 1 cm) and non-remission group (PGA > 1 cm). Anxiety was evaluated utilizing the Hospital Anxiety and Depression Scale-Anxiety (HADS-A), while depression was evaluated with HADS-Depression (HADS-D) and the Center for Epidemiologic Studies Depression Scale (CES-D). Comparison analyses were done between the PGA remission and non-remission groups in HADS-A, HADS-D and CES-D. RESULTS: Seventy-eight patients met the criteria for SJC ≤ 1, TJC ≤ 1 and CRP ≤ 1. There were no significant differences between the PGA remission group (n = 45) and the non-remission group (n = 33) in age, sex, disease duration and Steinbrocker's class and stage. HADS-A, HADS-D and CES-D scores were significantly lower in the PGA remission group. CONCLUSIONS: Patients with RA who did not meet the PGA remission criteria despite good disease condition were in a poorer psychological state than those who satisfied the Boolean-based definition of clinical remission. Psychological support might be effective for improvement of PGA, resulting in the attainment of true remission.

Improvement of health status evaluated by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36) in patients with rheumatoid arthritis treated with tocilizumab.

OBJECTIVE: To evaluate the improvement of health status in patients with rheumatoid arthritis (RA) treated with tocilizumab. METHODS: Thirty-nine patients were treated with 8 mg/kg tocilizumab every 4 weeks for 24 weeks. Disease activity was assessed by Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI). Improvement of health status was assessed by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36). RESULTS: Tocilizumab improved CDAI and SDAI significantly at week 4 compared with at baseline. In the components of AIMS-2, "physical score", "symptom" and "affect" improved significantly at week 4 compared with at baseline, while "social interaction" did not improve significantly during 24 weeks of tocilizumab therapy. Similarly in SF-36, "bodily pain", "general health", "vitality" and "mental health" improved significantly at week 4. The most correlative component of AIMS-2 with CDAI was "symptom", while "social interaction" did not correlate with CDAI during tocilizumab treatment. CONCLUSION: The time-course diversity in improvement of health status should be considered to provide proper healthcare when treated with tocilizumab.

[Tuberculous peritonitis during etanercept therapy for rheumatoid arthritis].

In August 2010, a 73-year-old woman with rheumatoid arthritis receiving etanercept (ETN) therapy for two years, developed high-fever and abdominal fullness. Though she had not been exposed to tuberculosis, isoniazid prophylaxis was administrated. Antibiotics were not effective. CT images revealed the massive ascites and peritonitis, and Ga scintigraphy demonstrated notable uptake in the peritoneum. Ascites analysis showed an elevated adenosine deaminase activity value (104.9 IU/l) without malignant cells. Moreover, PCR and culture for Mycobacterium tuberculosis were positive. Finally, a diagnosis of tuberculous peritonitis was established. After initiating a standard anti-tuberculosis regimen with four drugs, her clinical condition ameliorated and ascites promptly regressed. Although the tuberculous peritonitis during ETN therapy is rare, this report emphasized the importance of initial suspicion of tuberculosis in these patients with tumor necrosis factor inhibitors such as ETN.

The protective role of host Toll-like receptor-4 in acute graft-versus-host disease.

BACKGROUND: Mutations in Toll-like receptor (TLR)-4 have been associated with the hyporesponsiveness of macrophages to lipopolysaccharide, possibly reducing the risk of acute graft-versus-host disease (GVHD). However, TLR-4 mutations may also increase the risk of intestinal damage and microbial infection, thereby accelerating acute GVHD. METHODS: In this study, we investigated the role of TLR-4 in triggering acute GVHD using C3H/HeJ mice with disrupted TLR-4 and C3H/HeN mice with intact TLR-4 as recipients in an acute GVHD model. RESULTS: TLR-4 expression was significantly increased in the intestines and livers from acute GVHD mice. TLR-4-mutant C3H/HeJ hosts that received C57BL/6 (B6) donor cells developed significantly more severe GVHD than TLR-4-intact C3H/HeN hosts receiving B6 donor cells. Antibiotic treatment prolonged the survival of C3H/HeN-host GVHD mice but reduced the survival of C3H/HeJ-host GVHD mice. C3H/HeJ-host GVHD mice showed increased lipopolysaccharide levels in the blood, donor cell and CD68+ cell infiltration, tumor necrosis factor-α mRNA expression, and more apoptotic cells in the intestine compared with C3H/HeN host GVHD mice. In contrast, intestinal cyclooxygenase-2, prostaglandin E2, and hepatocyte growth factor expression in C3H/HeJ-host GVHD mice were significantly decreased compared with C3H/HeN-host GVHD mice. CONCLUSIONS: Our results indicated that host TLR-4 is crucial for the induction of tissue protective factors and for protection against intestinal cell apoptosis during acute GVHD.

Case of refractory otitis media with high-titer positive serum MPO-ANCA value.

A 56-year-old-woman presented a local otolaryngologist with a complaint of hearing loss. She was treated with antibiotics as acute otitis media, however her symptom did not improved. She admitted to our hospital because of hearing loss on both sides, fever, otorrhea and vertigo. On admission, an audiogram showed bilateral mixed conductive-sensorineural hearing loss, and CT image revealed the exudates in bilateral middle ear cavities and mastoid air cells. Moreover, serum level of myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) elevated (133EU). Although pulmonary, renal and cutaneous involvements were not noted and the histopathological examination of operated specimen taken from otitis media revealed non-specific inflammatory changes, in the absence of any other obvious causes of otitis media, these findings might be associated with positive serum MPO-ANCA value itself. After the initiation of therapy with methylprednisolone and azathioprine, her symptoms and hearing ability ameliorated and both CRP value and the titer of ANCA became normalized. But, after the improvement by the immunosuppressive treatment, MRSA in the otorrhea persisted. This case suggests that otitis media may be one of the symptoms of vasculitis, and some previous cases described otitis media or hearing loss as rare manifestations of vasculitis. It is important to make an early diagnosis for good prognosis of hearing ability, and we have to consider the differential diagnosis including of ANCA-related vasculitis.

CMV infection presenting as a cavitary lung lesion in a patient with systemic lupus erythematosus receiving immunosuppressive therapy.

We report a case of cytomegalovirus (CMV) pneumonitis that presented as a cavitary lung lesion in a patient with systemic lupus erythematosus receiving immunosuppressive treatment. The lesion was confirmed by positive polymerase chain reaction (PCR) for CMV in bronchoalveolar lavage fluid (BALF) and CMV antigenemia. PCR for CMV in BALF was demonstrated to be useful for the diagnosis of CMV pneumonitis on the basis of high sensitivity and specificity. After initiating ganciclovir, the lesion gradually regressed. A cavitary lung lesion associated with CMV is extremely rare. This presentation suggests that the differential diagnosis of cavitary lung lesion in immunocompromised individuals should include CMV.

[Quantitative evaluation of airway involvement in a patient with relapsing polychondritis using computed tomography].

A 63-year-old woman was admitted to our hospital because of auricular chondritis, conjunctivitis, polyarthralgia, productive cough and dyspnea. On admission, pulmonary function test demonstrated an obstructive pattern, and flow-volume curve (FVC) revealed a constrictive upper airway flow pattern. Chest CT showed a thickened tracheal wall and narrowing of the airway. The laboratory findings revealed an elevation of CRP and high titer of anti-type II collagen antibody. She was diagnosed as relapsing polychondritis (RP) according to Damiani's criteria. After the initiation of the therapy with 32 mg/day of methylprednisolone, her symptoms, pulmonary function, FVC and CT findings ameliorated promptly, and the titer of anti-type II collagen antibody became normalized. Moreover, we measured the airway wall thickness, percentage wall area (WA%) and percentage wall thickness (WT%), by CT and HRCT, and also evaluated the airway involvement quantitatively. Both WA% and WT% were inversely correlated with FEV1.0%. The airway inlolvement is most important prognostic factor in patients with RP, and sequential evaluation of airway manifestation are necessary. We suggest that a quantitative evaluation of bronchial structures by sequential CT is useful for the evaluation of RP as well as pulmonary function tests.

[A case of Achilles tendon rupture in a patient of refractory Reiter's syndrome].

We herein report a case of spontaneous rupture of Achilles tendon in a 51-year-old man with refractory Reiter's syndrome. On the diagnosis in November, 2006, physical examinations and MR images showed a remarkable inflammation at the calcaneal insertion area of Achilles tendon. He required aggressive treatments with nonsteroidal anti-inflammatory drug (NSAID), oral prednisolone 30 mg daily and methotrexate (8 mg weekly) to control the disease. Two months later, the Achilles tendon ruptured at its insertion point. This ruptured lesion of Achilles tendon was an unusual site compared to previous reports. Histological findings in the ruptured lesion of Achilles tendon revealed the existence of granulomatous lesion consisted of severe infiltration of fibroblasts and vessels proliferation beside tendon. These findings suggest a prolonged inflammation. Although it is widely accepted that Reiter's syndrome is associated with enthesis, especially at the attachment of Achilles tendon to calcaneum, there have been only two reports of Achilles tendon rupture associated with Reiter's syndrome. The possible cause of the Achilles tendon rupture in this patient might be due to the weakened strength of the Achilles tendon by the prolonged and severe enthesis of Achilles tendon near the insertion lesion.

Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 x DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 microg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC.

Hepatocyte growth factor preserves graft-versus-leukemia effect and T-cell reconstitution after marrow transplantation.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT). When GVHD is controlled by T-cell-depleted grafts or immunosuppressants, BM transplant recipients often suffer from an increased rate of leukemic relapse and impaired reconstitution of immunity. Using a mouse BMT model, we investigated the effects of hepatocyte growth factor (HGF) gene transfection on the severity of GVHD, the graft-versus-leukemia effect, and the reconstitution of T cells after BMT. After HGF gene transfer, acute GVHD was reduced, while mature donor T-cell responses to host antigens were preserved, resulting in a significant improvement of leukemia-free survival. HGF gene transfer promoted regeneration of bone marrow-derived T cells and the responsiveness of these cells to alloantigens. Furthermore, HGF preserved the thymocyte phenotype and thymic stromal architecture in mice with GVHD. This suggested that HGF exerts a potent protective effect on the thymus, which in turn promotes reconstitution of bone marrow-derived T cells after allogeneic BMT. These results indicate that HGF gene transfection can reduce acute GVHD preserving the graft-versus-leukemia effect, while promoting thymic-dependent T-cell reconstitution after allogeneic BMT.

Effect of FK506 on donor T-cell functions that are responsible for graft-versus-host disease and graft-versus-leukemia effect.

BACKGROUND: FK506 is a potent immunosuppressive agent that is used in human graft-versus-host disease (GvHD) prevention. However, the precise mechanisms for GvHD prevention and the effect on graft-versus-leukemia (GvL) activity are unknown. This study was undertaken to determine the effect of FK506, given at clinically relevant doses, on donor T-cell functions responsible for GvHD and GvL activity. METHODS: The effect of FK506 on GvHD prevention and GvL activity was investigated using a murine model of allogeneic bone-marrow transplantation in which mice were injected with a P815 leukemic cell line. The regulatory role of FK506 on donor T cells was tested by analysis of donor T-cell expansions in the spleen and donor anti-host T-cell proliferative and cytotoxic responses. mRNA expression of type 1 T helper (Th1), Fas ligand (L), and granzyme B were also evaluated in target organs of GvHD. RESULTS: FK506 significantly prolonged the survival of GvHD mice when given at the trough level of 17.6 ng/mL, whereas it also blocked GvL effect in P815-injected GvHD mice. FK506 reduced the expansion of donor CD8+ and, to a lesser extent, CD4+ T cells in the spleen and inhibited donor anti-host T-cell proliferative and cytotoxic responses. It also inhibited the induction of Th1, FasL, and granzyme B mRNA expression in target organs of GvHD. CONCLUSIONS: FK506 inhibits both GvHD and GvL activity when given at clinical doses by inhibiting donor T-cell expansion, donor anti-host T-cell reactivity, and Th1 immune responses.