Hideko Nakahara

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease.

Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including C-reactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with tocilizumab after tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity.

Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody.

Takayasu arteritis (TA) is a chronic inflammatory disease that involves the aorta and its major branches. Since overproduction of interleukin-6 (IL-6) seems to play a pathogenic role in TA, we used the anti-IL-6 receptor (IL-6R) antibody tocilizumab to treat a 20-year-old woman with refractory active TA complicated by ulcerative colitis (UC). Treatment with tocilizumab improved the clinical manifestations of TA and the abnormal laboratory findings in this patient and ameliorated the activity of UC. These results indicate that IL-6R inhibition with tocilizumab might be a future treatment option for TA.

Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab

Objectives: To understand the acute phase responses to surgical intervention in patients with rheumatoid arthritis (RA) treated with the anti-interleukin (IL)6 receptor antibody, tocilizumab. Methods: In a retrospective 1:1 pair-matched case-control study, 22 tocilizumab-treated RA cases and 22 cases treated with conventional disease-modifying antirheumatic drugs (DMARDs) and matched for type of surgery, age and sex were evaluated for body temperature every day, and blood C-reactive protein (CRP) levels and white blood cell (WBC), neutrophil and lymphocyte counts on days −1, 1, 3 and weeks 1 and 2 after joint surgery. Safety issues were also monitored. Results: No complications of infection or delay of wound healing occurred in either patient group. Tocilizumab partially, but significantly, suppressed the increase in body temperature on postoperative days 1 and 2, compared with DMARDs (average (SD) maximum increase in temperature was 0.45 (0.1)°C in the tocilizumab group and 0.78 (0.1)°C in the DMARD group; p<0.01). Tocilizumab completely suppressed the increase in CRP after surgery, whereas all cases treated with DMARDs showed a significant increase of CRP at postoperative day 1 (5.5 (0.6) mg/dl; p<0.001). WBC, neutrophil and lymphocyte counts showed no remarkable change after surgery, and there was no significant difference in any cell counts between the patient groups. Conclusions: Within this small number of cases, safe operations on patients were performed during tocilizumab treatment. Tocilizumab suppressed fever and increase of CRP after surgery, whereas there was no influence on the transition in number of leukocytes. This characteristic postoperative response should be considered during tocilizumab treatment.

Laboratory and febrile features after joint surgery in rheumatoid arthritis patients treated with tocilizumab

Objectives: To understand the acute phase responses to surgical intervention in patients with rheumatoid arthritis (RA) treated with the anti-interleukin (IL)6 receptor antibody, tocilizumab. Methods: In a retrospective 1:1 pair-matched case-control study, 22 tocilizumab-treated RA cases and 22 cases treated with conventional disease-modifying antirheumatic drugs (DMARDs) and matched for type of surgery, age and sex were evaluated for body temperature every day, and blood C-reactive protein (CRP) levels and white blood cell (WBC), neutrophil and lymphocyte counts on days −1, 1, 3 and weeks 1 and 2 after joint surgery. Safety issues were also monitored. Results: No complications of infection or delay of wound healing occurred in either patient group. Tocilizumab partially, but significantly, suppressed the increase in body temperature on postoperative days 1 and 2, compared with DMARDs (average (SD) maximum increase in temperature was 0.45 (0.1)°C in the tocilizumab group and 0.78 (0.1)°C in the DMARD group; p<0.01). Tocilizumab completely suppressed the increase in CRP after surgery, whereas all cases treated with DMARDs showed a significant increase of CRP at postoperative day 1 (5.5 (0.6) mg/dl; p<0.001). WBC, neutrophil and lymphocyte counts showed no remarkable change after surgery, and there was no significant difference in any cell counts between the patient groups. Conclusions: Within this small number of cases, safe operations on patients were performed during tocilizumab treatment. Tocilizumab suppressed fever and increase of CRP after surgery, whereas there was no influence on the transition in number of leukocytes. This characteristic postoperative response should be considered during tocilizumab treatment.

Anti-Interleukin-6 Receptor Antibody Therapy in Rheumatic Diseases

In the treatment of rheumatic diseases such as rheumatoid arthritis (RA) or systemic onset juvenile idiopathic arthritis (soJIA), new therapies targeting pro-inflammatory cytokines have been developed. IL-6 is a pleiotropic cytokine with a wide range of biological activities including a pro-inflammatory mediator activity. Overproduction of IL-6 has been reported to be pathologically involved in the rheumatic diseases and, therefore, blockade of IL-6 actions may improve the disease. Tocilizumab, a humanized monoclonal antibody against human interleukin-6 receptor (IL-6R), inhibits IL-6 binding to IL-6R and specifically interferes with IL-6 actions. Castlemans disease is an atypical lymphoproliferative disorder caused by the overproduction of IL-6. Tocilizumab therapy improves immunological and hematological abnormalities as well as systemic inflammatory symptoms including wasting. This translational study also confirmed the pathological significance of IL-6 in the disease. RA is a representative autoimmune inflammatory disease characterized by bone and cartilage destruction in multiple joints. Since IL-6 also plays pathological roles in RA, tocilizumab therapy has been introduced to the patients with refractory disease and has shown a strong therapeutic effect. Besides Castlemans disease and RA, tocilizumab has been shown to be effective for patients with soJIA and Crohns disease. Tocilizumab treatment is generally well tolerated and safe. Therefore, tocilizumab can be a promising therapeutic agent for the rheumatic diseases in which IL-6 overproduction is pathologically involved.

Cytologic finding of chyloascites in lymphangioleiomyomatosis. A case report.

BACKGROUND Lymphangioleiomyomatosis is a rare disease, histologically characterized by an abnormal proliferation of smooth muscle around the lymphatics. Lung is the most common site of involvement, and patients usually present with dyspnea, chest pain, and cough. Chylous pleural effusion and ascites occasionally appear during the course of the disease. There are only a few reports on the cytologic findings in this disease. To our knowledge, the cytologic findings of chylous pleural effusion and chyloascites have not been reported before. CASE A 23-year-old female presented with chylothorax, chyloascites and a retroperitoneal mass. Cytologic examination of chylous pleural effusion and chyloascites revealed numerous cohesive and thick clusters of cells with a high nuclear/cytoplasmic ratio, oval nuclei and slightly increased chromatin content. Mitosis and necrosis were not observed. Exploratory laparotomy and transbronchial lung biopsy were performed, and the histologic diagnosis was lymphangioleiomyomatosis involving the retroperitoneal lymph nodes, uterine fundus and lungs. Immunohistochemistry showed that the characteristic clusters in chylous fluids were positive for alpha-smooth muscle actin. CONCLUSION A diagnosis of lymphangioleiomyomatosis is possible from cytologic findings of effusions with the aid of clinical findings.

A case report of a patient with rheumatoid arthritis complicated withMycobacterium aviumduring tocilizumab treatment

Abstract A female patient with rheumatoid arthritis (RA) suffered from Mycobacterium avium (M. avium) infection during tocilizumab treatment. Tocilizumab was discontinued and she was treated with a recommended chemotherapy, resulting in improvement of M. avium. Tocilizumab retreatment did not aggravate M. avium infection, and radiographic abnormalities improved over 1 year after cessation of the recommended therapy. Tocilizumab may be one candidate for intractable RA patients with M. avium if any biologic is required.

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

Abstract 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 Steinbrockers 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.

AB0485 Tocilizumab is Effective for the Patient with Sjogren's Syndrome Complicated with Rheumatoid Arthritis

Background Interleukin-6 (IL-6) has been reported to be related with the pathogenesis of sjogrens syndrome (SS). However, there is no report clinically describing in detail that IL-6 inhibition is effective for SS. Objectives We evaluated the efficacy of tocilizumab (TCZ) for the patient with SS complicated with rheumatoid arthritis (RA). Methods Tocilizumab was administered at 8mg/kg every 4 weeks. Clinical, laboratory and image data were obtained from the records in our hospital. Results A 39-year-old woman was diagnosed as SS in 1997 and treated with 3 g/day of sodium bicarbonate and 3600 mg/day of potassium citrate because she was complicated with renal tubular acidosis (RTA) and hypokalemia. Her complaints were dry mouth and arthralgia. Laboratory findings under usage of sodium bicarbonate and potassium citrate were as follow: WBC 8600/mm3, Hb 12.1 g/dl, BUN 12 mg/dl, Cr 0.7 mg/dl, CRP 2.2 mg/dl, Na 138 mEq/l, K 3.5 mEq/l, and Cl 109 mEq/l. Antinuclear antibody titer was 1:320 with speckled pattern, and anti-SS-A and anti-SS-B antibodies was positive. RF and anti-CCP antibody were 45 IU/ml and >100 U/ml, respectively. Urine beta-2-MG level was markedly elevated to 15800 mg/l. Shirmers test was positive (right: 3mm, left: 1mm). Salivary flow rate in gum test was 0.29 ml/min and lip biopsy revealed extensive lymphocytic infiltration with fibrotic changes in salivary gland. Majority of infiltrating cells was T cells, in which, CD4+ T cells were predominantly seen rather than CD8+ T cells. Cytoplasma of duct and infiltrating cells were stained with anti-IL-6 antibody. Specimen of renal biopsy was almost comparable to that of lip biopsy including immuostaining. Regarding her RA, SJC, TJC and DAS28-CRP were 19, 23 and 6.38, respectively. Tocilizumab treatment was started in July, 2009 because she was refractory to conventional DMARDs and side effects. Tocilizumab normalized CRP at week 12. At week 24, TJC, TJC and DAS28-CRP improved to 4, 2 and 2.38 respectively and, thereafter, in remission. Salivary flow rate increased from 0.22 ml/min at baseline to 0.81 ml/min at week 24 in gum test. Urinary beta-2-MG decreased from 15800 mg/l to 1210 mg/l, thereafter, improved in normal level, while serum beta-2-MG levels did not change during 24 weeks of tocilizumab therapy. Second lip biopsy was performed after 2 years of tocilizumab therapy. Infiltration of inflammatory cells almost disappeared and cytoplasma of duct and residual cells were not stained with anti-IL-6 antibody. Ophthalmological consultation confirmed slightly improvement of Shirmers test (right: 4mm, left: 4mm) after 4 years of tocilizumab treatment. Tocilizumab therapy continued its efficacy for SS and RA and no side effect has been shown over 4 years. Conclusions This is the first report indicating the efficacy of tocilizumab for the patient with SS complicated with RA. Tocilizumab may be effective for preventing dysfunction of the salivary gland and inhibiting interstitial nephritis and, therefore, may be one candidate for SS patients with RA. References Grisius MM, et al. J Rheumatol 1997; 24: 1089-91. Halse A, et al. Scand J Immunol 1999; 49: 533-8. Fox RI, et al. J Immunol 1994; 152: 5532-9 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4416

Survey on attitudes regarding EULAR recommendations for the role of nurses involved in medical care of patients with chronic inflammatory arthritis in Japan.

Abstract Objective: We seek to evaluate the opinions of nurses and doctors in Japan regarding EULAR recommendations for nurses’ roles in the management of chronic inflammatory arthritis. Methods: This is a cross-sectional survey within Japan. We randomly selected nurses and doctors engaged in consultation of patients with rheumatoid arthritis (RA) and assessed their agreement and opinions on the feasibility of implementing EULAR recommendations, including potential barriers. Results: 431 nurses and 128 doctors completed the questionnaire. For both nurses and doctors, levels of feasibility showed statistically significant lower results compared with those of agreement for all items. When compared between nurses and doctors, agreement showed no statistically significant differences, while nurses’ answers were statistically significant lower for feasibility. Insufficient time, staff and knowledge, lack of established procedures and facilities, and lack of an education system for nurses were cited as barriers to the feasibility of implementing EULAR recommendations. Conclusions: This is the first survey within Japan evaluating opinions regarding EULAR recommendations for nurses’ roles. We found that while agreement was high, feasibility was generally believed to be low. We recommend further research and collaboration between medical professionals in order to implement these recommendations in Japan.