Masahiro Iwamoto

Pneumocystis jiroveci pneumonia in patients with rheumatoid arthritis treated with infliximab: A retrospective review and case–control study of 21 patients

OBJECTIVEnTo establish proper management of Pneumocystis jiroveci pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with infliximab. PCP has been observed in 0.4% of patients with RA treated with infliximab in Japan.nnnMETHODSnData from patients with RA (n = 21) who were diagnosed with PCP during infliximab treatment and from 102 patients with RA who did not develop PCP during infliximab therapy were collected from 14 rheumatology referral centers in Japan. A retrospective review of these patients and a case-control study to compare patients with and without PCP were performed.nnnRESULTSnThe median length of time from the first infliximab infusion to the development of PCP was 8.5 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 7.5 mg/day and 8 mg/week, respectively. Pneumocystis jiroveci was microscopically identified in only 2 patients, although the polymerase chain reaction test for the organism was positive in 20 patients. The patients with PCP had significantly lower serum albumin levels (P < 0.001) and lower serum IgG levels (P < 0.001) than the patients without PCP. Computed tomography of the chest in all patients with PCP revealed ground-glass opacity either with sharp demarcation by interlobular septa or without interlobular septal boundaries. Sixteen of the 21 patients with PCP developed acute respiratory failure, but all survived.nnnCONCLUSIONnPCP is a serious complication that may occur early in the course of infliximab therapy in patients with RA. For the proper clinical management of this infectious disease, physicians need to be aware of the possibility of PCP developing during infliximab therapy.

Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study

ObjectivesTo investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration.MethodsDisease activity was monitored for 56xa0weeks. The rate of continued efficacy was estimated by Kaplan–Meier curves.ResultsA total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8xa0years, preceding TCZ treatment period was 4.0xa0years and DAS28 was 1.5. The rate of continued LDA at 52xa0weeks was 13.4xa0% according to the Kaplan–Meier estimate. 19 patients (10xa0%) were completely drug-free and 17 patients (9.1xa0%) fulfilled DAS28 remission at 52xa0weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9xa0pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0xa0% at 52xa0weeks.ConclusionsTCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare.

Glucocorticoid and cyclosporine refractory adult onset Still’s disease successfully treated with tocilizumab

We report a 29-year-old Japanese woman with disseminated intravascular coagulation (DIC) and adult onset Still’s disease (AOSD). Her disease was refractory to high-dose glucocorticoids, two courses of steroid pulse therapy, and addition of cyclosporine (3.5xa0mg/kg/day). The serum interleukin-6 level was markedly elevated. Therefore, we administered an anti-interleukin-6 receptor antibody (tocilizumab, 8xa0mg/kg fortnightly), which dramatically improved her symptoms and the levels of acute-phase proteins. In addition, rapid tapering of the glucocorticoid dose was possible. Four months later, she was maintained on tocilizumab infusion once a month with low-dose steroid therapy. Cyclosporine is one of the first-line immunosuppressants for AOSD, especially when associated with DIC, hepatic failure, or hemophagocytic syndrome. In patients with cyclosporine-resistant AOSD, tocilizumab may be another useful option.

Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1β signaling and a poor clinical response

Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30–40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-naïve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6xa0months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-naïve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1β. IL-1β increased IL-33 expression markedly in FLS in vitro, compared to TNF-α. IL-1β might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.

Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs

To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease‐modifying antirheumatic drugs (DMARDs).

The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression

Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTX-naive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone. Methods MTX-naive, early RA patients with ≤12u2005months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1:1 to CZP+MTX or PBO+MTX for 52u2005weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52. Results 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3u2005months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p<0.001) and week 24 (mTSS CFB=0.26 vs 0.86; p=0.003). Clinical remission rates (Simple Disease Activity Index, Boolean and DAS28 (ESR)) of the CZP+MTX group were significantly higher compared with those of the PBO+MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX. Conclusions In MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms, demonstrating the efficacy of CZP in these patients. Trial registration number (NCT01451203).

A case of rheumatoid arthritis with protein losing enteropathy induced by multiple diaphragmatic strictures of the small intestine: successful treatment by bougieing under double-balloon enteroscopy

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most favoured for the treatment of rheumatoid arthritis (RA) but they sometimes induce inflammation and ulceration of the gastrointestinal tract.1 Approximately 75% of patients receiving long term NSAIDs develop inflammation in the small intestine that in rare cases results in protein losing enteropathy.2,3 Furthermore, NSAIDs can bring about diaphragmatic strictures in the small intestine as a consequence of ulcer healing.nnWe report here a patient with RA who had multiple diaphragmatic strictures in the small intestine and subsequent protein losing enteropathy, probably due to long term non-steroidal anti-inflammatory drugs use. Her intestinal stricture and protein losing enteropathy, however, were successfully corrected by bougieing under double balloon enteroscopy without resort to surgical resection.nnA 57 year old …

Steroid-refractory severe hepatic failure in adult onset Still's disease responding to cyclosporine.

We report two Japanese women with severe hepatic dysfunction and adult onset Still’s disease. A 51-year-old woman had been diagnosed with adult onset Still’s disease 3xa0years earlier. She relapsed while on maintenance therapy with prednisolone and methotrexate. After induction of remission with methylprednisolone pulse therapy, indomethacin, and methotrexate, severe hepatic failure occurred. This patient lacked the typical symptoms of adult onset Still’s disease. The second patient was a 32-year-old woman with typical adult onset Still’s disease. Remission was induced by high-dose prednisolone and methylprednisolone pulse therapy plus cyclosporine. After she stopped cyclosporine, severe liver dysfunction occurred. In both patients, liver dysfunction occurred during high-dose steroid therapy, and oral cyclosporine (3xa0mg/kg per day) dramatically improved their liver function. When steroid-resistant severe hepatic failure occurs in patients with adult onset Still’s disease, cyclosporine may be the immunosuppressant of choice.

Prognostic indicators related to death in patients with Pneumocystis pneumonia associated with collagen vascular diseases

The objective of this study is to investigate the clinical markers of life-threatening Pneumocystis pneumonia (PCP) in patients with collagen vascular diseases (CVD). The patients who contracted Pneumocystis jeroveccii were retrospectively selected from our medical charts and conditions related to the patients’ death were reviewed. The findings indicated that lower levels of serum albumin and cholinesterase, increased alveolar–arterial oxygen gradient, intratracheal intubation, and necessity to treat in the intensive care unit were significantly related to deaths associated with PCP in CVD. A special attention should be paid to decreased serum albumin and cholinesterase as ominous predictors in PCP occurred in patients with CVD.

Monoclonal Antibody Against Citrullinated Peptides Obtained From Rheumatoid Arthritis Patients Reacts With Numerous Citrullinated Microbial and Food Proteins

To investigate the reactivity of monoclonal anti–citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of rheumatoid arthritis (RA) patients with human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA.