Tocilizumab monotherapy for large vessel vasculitis: results of 104-week treatment of a prospective, single-centre, open study.

OBJECTIVE: To evaluate the efficacy and safety of tocilizumab (TCZ) monotherapy for large vessel vasculitides (LVV), including Takayasu arteritis (TAK) and GCA. METHODS: Twelve patients with a newly diagnosed LVV (eight GCA, four TAK) were enrolled. One TAK patient withdrew consent, so 11 (eight GCA, three TAK) were analysed in a prospective, open-label study. TCZ (8 mg/kg) monotherapy, without glucocorticoids or immunosuppressants, was administered every 2 weeks for 2 months and then every 4 weeks for 10 months. Patients were followed for 1 year after the final TCZ dose. Complete and partial responses were defined as disappearance or improvement of all clinical symptoms and normalization of CRP. Relapse was defined as the worsening or recurrence of clinical symptoms, increase in CRP attributable to vasculitis, and/or the need for initiation of glucocorticoids and/or immunosuppressants. Poor clinical response described patients who did not fit the definition of complete response or partial response. RESULTS: Complete and partial responses rates were 75/66% and 25/0% in GCA/TAK patients, respectively, at week 24 and week 52. Five GCA patients and one TAK patient remained disease-free for 1 year after therapy. One GCA patient required TCZ discontinuation due to heart failure at week 24. CONCLUSION: TCZ monotherapy showed a high response rate for newly diagnosed LVV patients, and the majority of patients did not relapse for 1 year after TCZ cessation. Result of this study could help us to understand the crucial role of IL-6 in the pathogenesis of LVV.

Tocilizumab monotherapy for polymyalgia rheumatica: A prospective, single-center, open-label study.

OBJECTIVES: Polymyalgia rheumatica (PMR) is a systemic inflammatory disease in the elderly of unknown etiology. While glucocorticoids are the mainstay of treatment for PMR, various glucocorticoid-related adverse events are common. Recently, several studies have reported the efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, for PMR treatment in addition to an accompanying reduction, or even tapering-off, of glucocorticoids in some cases. The objective of this study was to elucidate the efficacy of TCZ monotherapy in the absence of glucocorticoids for PMR. METHOD: We conducted a 2-year, prospective, single-center, open-label pilot study of TCZ monotherapy in patients with PMR. TCZ (8 mg/kg) was administered at fortnightly intervals for the first 2 months and monthly over the next 10 months. Subsequently, patients were observed for another year without any treatment. The primary endpoints were the remission rates at weeks 12 and 52, and the secondary endpoints were the relapse rate and safety over the total 104 weeks. RESULTS: Thirteen patients were included in this study. Four of these patients achieved remission at week 12 (remission rate 31%). Four patients withdrew from the study due to adverse events (n = 2) and inefficacy (n = 2). At week 52, all 9 patients who had completed the first year achieved remission. Eight patients completed the drug-free second year, with 7 maintaining remission. CONCLUSIONS: TCZ monotherapy is well tolerated and can lead to remission in most patients with PMR in the absence of glucocorticoids.

Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis.

OBJECTIVES: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. METHODS: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 - erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. RESULTS: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. CONCLUSION: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

Current clinical evidence of tocilizumab for the treatment of ANCA-associated vasculitis: a prospective case series for microscopic polyangiitis in a combination with corticosteroids and literature review.

The purpose of this study is to report the efficacy and safety of a combination of tocilizumab (TCZ) and high-dose corticosteroid (CS) in two patients with microscopic polyangiitis (MPA) and review the published current clinical evidence on TCZ in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), except for large vessel vasculitis (LVV) and polymyalgia rheumatica (PMR). Two MPA patients were treated with TCZ at 8 mg/kg every month for 1 year and CS (prednisolone 1 mg/kg/day for 2 weeks, followed by tapering) in a prospective single-arm, single-center, cohort, open-label pilot study (UMIN clinical trials: 000012072). We performed a systematic literature search (PubMed and ICHUSHI [Japan Medical Abstracts Society] until June 30, 2017) to identify published reports on patients with all vasculitis other than LVV/PMR, who were treated with TCZ. We successfully treated the first patient. However, the other patient had serious infection probably associated with the combination of TCZ and high-dose CS. The literature review identified 22 reports with a total of 34 patients who received TCZ for AAV, rheumatoid vasculitis, and other types of vasculitis, in addition to our patients. In 15 of 17 patients (88.2%) with primary and secondary AAV, especially MPA, TCZ induced clinical remission, although TCZ use for rheumatoid vasculitis and vasculitis with mucocutaneous lesions is controversial. This study suggested that TCZ therapy is a potential treatment strategy for patients with AAV. However, TCZ combined with high-dose of CS might not be an appropriate treatment. Future studies are needed to confirm our findings.

Corticosteroid-free treatment of tocilizumab monotherapy for microscopic polyangiitis: a single-arm, single-center, clinical trial.

OBJECTIVES: To assess the efficacy of tocilizumab (TCZ) monotherapy for the remission induction of microscopic polyangiitis (MPA) in a prospective single-arm, single-center, cohort, pilot study. METHODS: Eligible patients were aged between 20 and 80 years and were newly diagnosed with MPA according to Watts' classification algorithm. Seven patients received 8 mg/kg of intravenous TCZ fortnightly for the first 2 months (5 courses), and monthly for the next 10 months (10 courses). One year after TCZ monotherapy, the patients were followed-up without any treatment. The protocol did not permit the use corticosteroids or any other immunosuppressants. Complete remission (CR) was defined as the Birmingham Vasculitis Activity Score of 0 at two consecutive visits made at least a month apart. RESULTS: CR was achieved in two of six patients (33.3%) at 6 months and three patients (50.0%) at 12 months. Two patients were withdrawn: one because of inefficacy at 6 weeks and the other because of flare at 6 months. One patient voluntarily withdrew after CR at 3 months. Four patients (66.7%) could be kept drug-free after 1 year of TCZ without relapse for 6-15 months at the last visit. CONCLUSION: TCZ monotherapy may be an alternative treatment strategy in some patients with MPA.

Successful treatment of class IV+V lupus nephritis with combination therapy of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide.

A substantial number of patients with lupus nephritis (LN) are refractory to conventional glucocorticoid (GC) treatment. Although many of these patients respond to immunosuppressive drugs such as intravenous cyclophosphamide (IVCY), azathioprine (AZA), mizoribine, tacrolimus, cyclosporine A (CSA) and mycofenolate mofetil (MMF), some remain refractory to such therapies. Recent studies of multi-target therapies have reported effective outcomes for immunosuppression following renal transplantation and refractory LN when therapy consists of two or more immunosuppressive drugs with different mechanisms of action. We herein report a case of LN unresponsive to IVCY that was successfully treated with the addition of tacrolimus and discuss the usefulness of multi-target therapy for LN.

Efficacy of weekly mizoribine pulse therapy in refractory lupus nephritis.

OBJECTIVE: We investigated the efficacy of a high-dose intermittent dosing treatment method (weekly mizoribine pulse therapy) conceived in the hope of achieving better efficacy by increasing the peak blood levels of mizoribine in patients with refractory lupus nephritis. METHODS: Seventeen patients with lupus nephritis who had been resistant to corticosteroid and immunosuppressant therapy received weekly mizoribine pulse therapy. Mizoribine (350 mg) was administered three times at 12 h intervals over 2 consecutive days (700 mg for day 1 and 350 mg for day 2), followed by a washout period from day 3 to day 7. RESULTS: This therapeutic strategy enabled the peak blood levels of mizoribine to be increased to more than 3 µg/mL in most of the patients. Although SLEDAI, anti-ds-DNA antibody titer, CH-50, and serum albumin level did not significantly improve, urinary protein levels decreased, and it was possible to taper the dose of concomitant steroids. Using our definition of clinical response, 10 of the 17 patients were responders and 4 of them were nonresponders. The average peak serum mizoribine concentration of the responders was as high as 3.5 µg/mL. Elevation of serum liver enzymes was seen in 1 patient, and hyperuricemia occurred in 4 cases, but none of these adverse events were serious. CONCLUSION: Intermittent administration of mizoribine can increase blood levels and may be effective for refractory lupus nephritis.

A case of multiple giant coronary aneurysms and abdominal aortic aneurysm coexisting with IgG4-related disease.

IgG4-related disease (IgG4RD) is a unique systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and IgG4-producing plasma cell expansion in the affected tissues, which are accompanied by fibrotic or sclerotic changes. Vascular lesions may also be a part of IgG4RD as a number of case reports have discussed inflammatory abdominal aortic aneurysms associated with IgG4RD, but coronary artery lesions seem to be rare complications of IgG4RD. A 71-year-old man suffered from multiple giant coronary aneurysms and an abdominal aortic aneurysm with concurrent pancreatic, gall bladder, bile duct, and salivary gland lesions resulting from IgG4RD. The present observations suggest that coronary aneurysms may also develop as a consequence of this disease.

Successful treatment of adult-onset Still's disease with tocilizumab monotherapy: two case reports and literature review.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recently, it has been reported that quite a few cases of refractory AOSD were successfully treated with tocilizumab (TCZ) and corticosteroids were withdrawn in some of these patients. We report two AOSD patients who were treated successfully with TCZ monotherapy; thus, avoiding corticosteroid treatment. Because both of the patients refused to take corticosteroids, we planned to treat them with 8 mg/kg of TCZ monotherapy at weeks 0, 2, 6 and subsequently every 4 weeks. The efficacy of TCZ was assessed by patients' clinical symptoms such as fever, arthralgia, skin eruptions, and laboratory markers such as serum levels of CRP, ferritin, and IL-6. We also reviewed 14 previous case reports including 30 cases who had been treated with TCZ for AOSD. Our patients responded rapidly and have been maintained in clinical remission without corticosteroid treatment. In the literature review, concomitant corticosteroid treatment described in 13 cases was successfully tapered in 7 and discontinued in 6 cases. TCZ monotherapy can be a candidate for the first-line therapy for some AOSD patients.

Single center prospective study of tacrolimus efficacy and safety in the treatment of various manifestations in systemic lupus erythematosus.

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) in various manifestations of systemic lupus erythematosus (SLE) patients in daily clinical practice. Each of the 21 TAC-treated patients with SLE in our care over 2 years was enrolled in this open-label trial. Patients were administered TAC at a dosage of 1-6 mg once daily, followed up for 24 weeks. Efficacy and safety were evaluated utilizing clinical and laboratory findings. As treatment targets, TAC was preferentially used with oral corticosteroid administration for mild active manifestations such as arthritis, skin eruptions, or asymptomatic nephritis. In efficacy, the mean value of the SLE disease activity index was significantly reduced to 4.1, 2.7, 1.8, and 1.2 (N=21, 20, 16 and 13) at 0, 4, 12, and 24 weeks, respectively. In eight cases, treatment was discontinued within 24 weeks due to insufficient effects (6 cases) and side effects (2 cases). Non-serious side effects were observed in only five cases (23.8%) over 24 weeks. TAC can be considered both effective and safe for the treatment of various manifestations of SLE.

Notable difference between the development of vertebral fracture and osteonecrosis of the femoral head in patients treated with high-dose glucocorticoids for systemic rheumatic diseases.

OBJECTIVE: Vertebral fracture (VF) and osteonecrosis of the femoral head (OFH) are serious concerns in patients with rheumatic diseases treated with high-dose glucocorticoids (GCs). We comparatively examined the risk factors of VF and OFH in patients who had recently received high-dose GC therapy. PATIENTS AND METHODS: Patients with rheumatic diseases receiving GCs (> or =0.5 mg/kg/day for prednisolone equivalent) within the past 2 months were enrolled in this study, and treated with 200 mg/day of etidronate cyclically. The bone mineral density (BMD) of the lumbar spine (L2-4) was examined by QDR2000. OFH was evaluated by magnetic resonance imaging (MRI). [ClinicalTrials.gov identifier: NCT00679978]. RESULTS: Forty-four patients completed the 2-year study including annual X-rays and the BMD analysis. MRI evaluation at entry and 2 years was performed in 41 patients. The BMD values with anteroposterior (AP) and lateral views decreased by 6.4% and 9.7%, respectively, in the first year, but were stable in the second year. Eleven patients developed VF and 9 patients developed OFH. The risk factors for VF included previous VF and a low BMD value (T score<-1.5) of AP view at baseline with an odds ratio (OR) of 14.9 (95%CI 2.9-76.4), while the risk factor for OFH was a recent maximum GC dosage (>1.2 mg/kg/day versus< or =; OR=7.7, 95%CI 1.3-45.5) and a decrease in BMD value of lateral view (>15% versus< or =; OR=6.7, 95% CI 1.2-36.1) in the first year. CONCLUSION: The development of VF relies on the predisposing factors, while that of OFH depends on the response to high-dose GC therapy.

Single center prospective study of tacrolimus efficacy and safety in treatment of rheumatoid arthritis.

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus for treating rheumatoid arthritis (RA) patients in clinical practice. Fifty-five active RA patients who had been resistant or intolerant to other disease-modifying antirheumatic drugs were enrolled in this open-label trial. Patients were administered tacrolimus at a dosage of 1, 2 or 3 mg once daily, and followed up for 24 weeks. They were divided into three groups according to their dosage. Efficacy and safety were evaluated utilizing clinical and laboratory findings. Eighty percent of the patients had moderate or high disease activity; 55% were elderly and 53% had complications; 65% of the patients were started on tacrolimus as a monotherapy. Moderate or good response rates were achieved as follows: 38.2% (4 weeks); 41.8% (12 weeks); and 45.6% (24 weeks). Adverse events were observed in seven cases (12.7%). Only one case required hospitalization due to severe hyperglycemia caused by a high tacrolimus concentration (24.2 ng/ml); we suspected a drug interaction in this subject. Mean concentrations were dose-dependent in the 1, 2, and 3 mg/day groups (2.96, 4.29, and 8.32 ng/ml, respectively). Four cases of high concentration (over 10 ng/ml), without any signs or symptoms, were observed in the 3 mg/day group; in these cases, doses were decreased and no severe adverse events occurred. Tacrolimus was found to be both effective and safe in treating active RA patients with complicated backgrounds in clinical practice. Blood concentration measurements and dose adjustments should be performed to prevent severe adverse events in a 3 mg/day group.

Prospective study of low-dose cyclosporine A in patients with refractory lupus nephritis.

We evaluated the efficacy and safety of low-dose cyclosporine A (CsA) in patients with refractory lupus nephritis. Nine patients with systemic lupus erythematosus who had lupus nephritis resistant to previous treatment with glucocorticoids and immunosuppressants other than CsA were enrolled in a prospective, open-label study. All patients initially received 2.5 mg/kg per day of CsA; the dosage was adjusted to reach a blood trough level of 80-150 ng/ml. The urinary protein concentration decreased significantly 2 weeks after the initiation of treatment. After 30 weeks of CsA treatment, the mean urinary protein concentration was more than 50% lower than the baseline value, and urinary casts had decreased significantly. There were no significant changes in the levels of serum creatinine, serum anti-double-stranded DNA antibodies, or CH50 during any part of the study. The dose of glucocorticoids was significantly tapered by approximately 50%, without any disease flare. Hypertension developed in one patient, but was controlled with antihypertensive agents. Our results suggest that low-dose CsA therapy is an effective and less toxic alternative to conventional cyclophosphamide therapy for the management of refractory lupus nephritis.

Development and validation of handy rheumatoid activity score with 38 joints (HRAS38) in rheumatoid arthritis patients receiving infliximab.

The parameters involved in the Disease Activity Score of 28 joints (DAS28) are not mutually independent, and the evaluation excludes ankle and foot joints. We developed a new quantitative and comprehensive assessment of the activity of rheumatoid arthritis (RA), called the handy rheumatoid activity score, with 38 joints (HRAS38), to overcome these disadvantages of DAS28. Forty-six RA patients who recently completed a 1-year infliximab therapy were evaluated for DAS28 (C-reactive protein; CRP) and HRAS38 at 0, 2, 6, 14, 22, 30, 38, 46, and 54 weeks. The 38-joint evaluation in HRAS38 includes 28 joints of DAS28 except for the shoulder joints, with the addition of ankle and metatarsophalangeal joints. The extent of joint swelling was rated on a scale of 0-3. The HRAS38 score is the cumulative sum of three parameters including: (1) a global assessment of disease activity [visual analog scale (VAS) 0-100 mm] by the patient, (2) swollen joint score based on a 38-joint assessment by a physician (0-114), and (3) serum concentration of CRP (mg/l). Scatter plots of HRAS38 and DAS28(CRP), and subsequent linear regression analysis demonstrated a statistically significant correlation between methodologies (r = 0.846, P < 0.0001). Infliximab treatment resulted in a statistically significant (P < 0.001) decrease in the mean HRAS38 score from 130.5 to 56.5 within 2 weeks of treatment and at 52 weeks of therapy scores were still reduced at 52.5. The mean DAS28(CRP) was also significantly (P < 0.001) reduced from a baseline value of 5.8 to 3.7 after 2 weeks treatment with a final value of 3.2 after 52 weeks of therapy. Infliximab reduced the progression of joint destruction by 85%, for terms before infliximab as determined by radiographic analyses. The degree of progression appeared to be associated with the mean HRAS38, although this observation was not shown to be statistically significant by regression analysis (r = 0.307). The HRAS38 score comprises minimal and independently acquired parameters and is an effective and comprehensive measure of disease activity in RA patients.

Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis.

OBJECTIVE: Acute/subacute interstitial pneumonia (A/SIP) in patients with polymyositis/dermatomyositis (PM/DM) is frequently fatal within months despite high dose prednisolone (PSL) therapy. Our objective was to improve the survival rate of patients with A/SIP associated with PM/DM; and to characterize patients with PM/DM who are at high risk of developing A/SIP. METHODS: We conducted a pilot trial of combined immunosuppressive therapy with high dose PSL, 10-30 mg/kg of intravenous pulse cyclophosphamide (IVCYC) every 3-4 weeks, and 2-4 mg/kg/day of cyclosporin A (CSA) for patients with A/SIP. A/SIP was diagnosed based on a history of rapidly worsening respiratory symptoms, progressive radiological findings or hypoxemia, and compatible findings in high resolution computed tomography images. RESULTS: Before December 2000, 12 patients with DM among 83 PM/DM patients developed A/SIP, and 9 patients died despite treatment using high dose PSL with or without a choice of CSA, cyclophosphamide, or azathioprine. Thereafter, 10 patients with DM among 27 PM/DM patients developed A/SIP, and they were given combination therapy with PSL, CSA, and IVCYC. Five patients survived and are doing well for more than 2 years, although the remaining 5 patients died of respiratory failure within 3 months. DM patients with A/SIP showed the following characteristic features: mild myositis, palmar papule, fever, and negative or low titer of antinuclear antibody. CONCLUSION: Immediate institution of intensified immunosuppressive therapy should be considered for patients with A/SIP complicating DM. However, even early recognition of A/SIP and immediate commencement of a regimen including CSA and IVCYC in addition to high dose PSL may not be sufficient for some of those patients.

Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy.

OBJECTIVE: To evaluate the incidence and effect of cytomegalovirus (CMV) reactivation in patients with inflammatory connective tissue diseases (CTD) undergoing immunosuppressive therapy. METHODS: A total of 18 consecutive CMV seropositive patients undergoing immunosuppressive therapy for inflammatory CTD were enrolled. CMV reactivation was determined by detection of CMV-DNA in peripheral blood leukocytes (PBL) or plasma using quantitative real-time polymerase chain reaction. RESULTS: CMV reactivation was detected in PBL in 7 of 17 evaluable patients (41%), and in plasma in 5 of 17 patients (29%). Patients with detectable CMV-DNA in plasma were exclusively positive for CMV-DNA in PBL. Conclusion. Patients with inflammatory CTD under immunosuppressive therapy are at high risk for CMV reactivation. The clinical significance of such an event and indications for antiviral therapy should be examined further.

Factors predicting the response to low-dose methotrexate therapy in patients with rheumatoid arthritis: a better response in male patients.

Abstract Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) throughout the world. In Japan, MTX is recommended by the Japanese Ministry of Health, Labour, and Welfare to be given as the second or third DMARD and at a dosage of no more than 8 mg/week. We analyzed the efficacy of MTX in Japanese patients with RA in order to determine whether it is comparable to that in Western countries, where 15-20 mg/week of MTX is used, as well as to elucidate the factors associated with the favorable response to MTX. Around 8 mg/week of MTX was effective in half of the RA patients in the current study, and male sex was the only factor associated with a good response to MTX from a multivariate regression model analysis. Some of the patients who had a poor response to MTX showed an improvement with the addition of bucillamine or prednisolone. For the remaining patients, an increase in the MTX dosage to more than 8 mg/week or the use of biologics such as the anti-tumor necrosis factor (TNF)-α monoclonal antibody may be required.