Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: Results from a randomized phase II trial.

OBJECTIVES: This phase II, dose-ranging, double-blind, placebo-controlled, randomized study (NCT01463059) evaluated efficacy and safety of olokizumab (OKZ), a humanized anti-interleukin 6 monoclonal antibody, in Asian patients with moderately-to-severely active rheumatoid arthritis (RA) who had previously failed anti-TNF therapy. METHODS: Patients were randomized to one of six treatment arms: placebo or OKZ (60 mg/120 mg/240 mg every four weeks [Q4W]; or 60 mg/120 mg every two weeks [Q2W]); stratified by country and number of prior anti-TNFs. Primary efficacy variable was Week 12 change from baseline (CFB) in DAS28 CRP for 4-week cumulative dose groups of OKZ and placebo; secondary efficacy variables were Week 12 ACR20/ACR50/ACR70 response rates. Patients continued MTX treatment from baseline, without additional csDMARDs. RESULTS: Of 119 randomized patients, 88.2% completed the study. Greater improvements in DAS28(CRP) mean CFB at Week 12 were observed in all OKZ 4-week cumulative dose groups (60 mg/120 mg/240 mg) versus placebo (p < 0.0001). Week 12 ACR20/ACR50 response rates were higher in all OKZ cumulative dose groups versus PBO (p < 0.05). Incidences of adverse events were similar across OKZ 4-week cumulative dose groups (76.9-84.4%) and placebo (82.8%) with no deaths. CONCLUSIONS: OKZ demonstrated improvements in efficacy variables versus placebo in Asian patients with moderately-to-severely active RA who had previously failed anti-TNF therapy. The safety profile was as expected for this class of drug.

Effectiveness of etanercept vs cyclophosphamide as treatment for patients with amyloid A amyloidosis secondary to rheumatoid arthritis.

OBJECTIVES: To compare the effectiveness of an alkylating agent with that of a biologic agent in the treatment of patients with amyloid A (AA) amyloidosis secondary to RA and to assess the association of the serum AA (SAA) 1.3 allele with treatment. METHODS: CYC and etanercept (ETN) were administered to 62 and 24 RA patients, respectively, who were confirmed with biopsy as having AA amyloidosis. We evaluated whether the SAA1.3 allele, a factor indicating genetic risk and poor prognosis of Japanese RA patients with AA amyloidosis, influenced treatments and retrospectively analysed the effectiveness of both agents via statistical methods. RESULTS: Two treatment groups were similar, except for the SAA1.3 genotype (P = 0.015) and duration of AA amyloidosis since diagnosis (P < 0.001). Also, patients given ETN had somewhat worse renal function, i.e. 24-h proteinuria (P = 0.02), at the initiation of treatment. ETN demonstrated greater effectiveness than CYC, as shown by significantly improved levels of serum CRP and serum albumin (both P < 0.01) and estimated glomerular filtration rate (eGFR; P = 0.032). ETN improved survival (P = 0.025), and the hazard ratios for the risk of death endpoint with eGFR and 24-h proteinuria were significant by P = 0.024 and P = 0.025, respectively. The SAA1.3 allele did not affect the response to medications in AA amyloidosis secondary to RA. CONCLUSION: ETN treatment was more effective than CYC treatment, and CRP, albumin and eGFR may be valuable biomarkers for analysis. The SAA1.3 allele was not a factor affecting treatment in Japanese patients with AA amyloidosis secondary to RA.

Continuation of methotrexate resulted in better clinical and radiographic outcomes than discontinuation upon starting etanercept in patients with rheumatoid arthritis: 52-week results from the JESMR study.

OBJECTIVE: The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA). METHODS: In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6-8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score. RESULTS: The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (-0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively). CONCLUSION: MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103).

Cutaneous nodules in patients with rheumatoid arthritis: a case report and review of literatures.

We report a case of 57-year-old Japanese woman with an overlap syndrome of both rheumatoid arthritis (RA) and autoimmune hepatitis, who developed multiple skin nodules. An extensive biopsies of the nodules revealed rheumatoid neutrophilic dermatitis, showing panniculitis without vasculitis, combining with granulomatous formation histopathologically. Since cutaneous nodules in patients with RA are very complex, differential diagnosis should be done according to disease activities, medications used, and pathological findings. We suggest that the differences in histopathological findings of cutaneous nodules in patients with RA depend on their immunological conditions based on disease activities including therapeutic effects.

Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial.

The superiority of the combination therapy of methotrexate (MTX) and anti-tumor necrosis factor (TNF) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis (RA) has been demonstrated. We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept (ETN) in patients with active RA despite MTX therapy. In total, 151 patients with active RA despite treatment with MTX were randomized to either ETN 25 mg twice a week and MTX 6-8 mg/week (the E + M group) or ETN alone (the E group). Co-primary endpoints included the European League Against Rheumatism (EULAR) good response rate and the American College of Rheumatology (ACR) 50 response rate at week 24. Demographic and clinical features between groups at baseline were similar. The EULAR good response rates were significantly higher in the E + M group (52%) than in the E group (33%) at week 24 (p = 0.0001). Although the ACR50 response rate, one of the co-primary endpoints, and the ACR70 response rate at week 24 were not significantly greater in the E + M group (64 and 38%, respectively) than in the E group (48 and 26%, respectively), the ACR20 response rate was significantly greater in the E + M group (90%) than in the E group (64%; p = 0.0002). Safety profiles were similar for the groups. Thus, MTX should be continued at the commencement of ETN therapy, even in RA patients who show an inappropriate response to MTX.

Etanercept can induce resolution of renal deterioration in patients with amyloid A amyloidosis secondary to rheumatoid arthritis.

The benefit of biological therapies in rheumatoid arthritis (RA) treatment is well known, but their role in amyloid A (AA) amyloidosis secondary to RA is unclear. The aim of this study was to clarify the clinical benefit of etanercept in RA patients with AA amyloidosis. We treated 14 RA patients who had serum amyloid A protein (SAA) 1.3 allele, with biopsy-confirmed AA amyloidosis with etanercept and investigated the efficacy of etanercept treatment, focusing on renal function retrospectively. The AA amyloidosis improved and stabilized after 89.1 ± 27.2 weeks. Proteinuria decreased from 2.24 ± 0.81 to 0.57 ± 0.41 g/day (P < 0.01) and SAA fell from 250 ± 129 to 26 ± 15 µg/ml (P < 0.01), respectively. Diarrhea secondary to gastrointestinal AA amyloidosis was less. Overall, the serum creatinine levels did not benefit with treatment, but in those with a creatinine values <2.0 mg/dl the creatinine level continued to fall (P = 0.021). Serum albumin increased following 96 weeks of etanercept treatment (P = 0.003). Etanercept treatment led to clinical improvement in proteinuria and serum albumin levels accompanied by a fall in SAA levels.

Synoviocyte-derived angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarticular synovitis of the diarthrodial joints. Several proinflammatory cytokines derived from both infiltrating inflammatory cells and activated resident cells within the RA joint play a fundamental role in the processes that cause inflammation. However, anticytokine treatment is beneficial but not curative, the effects are only partial, and nonresponses are common. Therefore, an effort has been made to identify other key regulators of inflammation in articular structures to develop new therapies to suppress synovial inflammation and joint destruction in RA. Adipose tissue-derived angiopoietin-like protein 2 (Angptl2) activates an inflammatory cascade in endothelial cells and induces chemotaxis of monocytes/macrophages in obesity, resulting in initiation and propagation of inflammation within adipose tissues and obesity-related metabolic diseases. Angptl2 mRNA and protein are abundantly expressed in hyperplastic rheumatoid synovium of RA patients, especially in fibroblast-like and macrophage-like synoviocytes, but not in B and T lymphocytes. Angptl2 concentration in joints of RA patients was also significantly increased in comparison with patients with osteoarthritis, which in comparison with RA represents a significantly lower inflammatory grade form of arthritis. Notably, Angptl2 promoted increased chemotactic activities of CD14+CD16- monocytes from synovial fluid of RA patients. Therefore, Angptl2 acts as an important rheumatoid synovium-derived inflammatory mediator in RA pathogenesis.

Beneficial effect of galectin 9 on rheumatoid arthritis by induction of apoptosis of synovial fibroblasts.

OBJECTIVE: To compare the expression of galectin 9 (Gal-9) in synovial tissue (ST) from rheumatoid arthritis (RA) patients and osteoarthritis (OA) patients and to evaluate the effects of Gal-9 on fibroblast-like synoviocytes (FLS) in these patients. METHODS: The expression of Gal-9 in ST and FLS was compared using immunohistochemical techniques. Apoptotic cells in RA and OA ST samples were detected by TUNEL assay. Apoptosis of FLS was analyzed by the sub-G(1) method in vitro. The in vivo suppressive effects of Gal-9 on collagen-induced arthritis (CIA) in a mouse model were also elucidated. RESULTS: The percentage of Gal-9-positive cells in ST samples and the amount of Gal-9 in synovial fluid samples were significantly higher in patients with RA than in patients with OA, suggesting the involvement of Gal-9 in the development of RA. Compared with the 2 wild-type Gal-9 forms, stable Gal-9, a mutant protein resistant to proteolysis, significantly induced apoptosis of FLS from RA patients. In contrast, other galectins, such as Gal-1, Gal-3, and Gal-8, did not induce apoptosis or suppress the proliferation of human RA FLS. Stable Gal-9 preferentially induced apoptosis and suppressed the proliferation of RA FLS in vitro. It also induced apoptosis of cells in RA ST implanted into SCID mice in vivo. In a mouse model of CIA, apoptotic cells were detected in the joints of stable Gal-9-treated mice, but not phosphate buffered saline-treated mice, and suppressed CIA characterized by pannus formation with inflammatory cell infiltration and bone/cartilage destruction. CONCLUSION: Gal-9-induced apoptosis of hyperproliferative RA FLS may play a critical role in the suppression of RA.

CD8+ T lymphocytes infiltrate predominantly in the inflammatory foci of MPO-ANCA-positive thoracic hypertrophic pachymeningitis in a patient with HLA-A24.

Hypertrophic pachymeningitis (HP) is extremely rare and an inflammatory process that thickens the dura mater. A 59-year-old Japanese woman developed backache, became paraplegic, and magnetic resonance imaging revealed diffuse thickening of the thoracic dura mater encompassing the spinal cord. Although a test for myeloperoxidase antineutrophil cytoplasmic autoantibody (MPO-ANCA) was shown to be positive, vasculitis was not found and CD8(+) T lymphocytes that predominated in the inflammatory foci. Both interleukin (IL)-2 and IL-6 were markedly elevated in not only sera but also cerebrospinal fluids, very much higher in the latter. Human leukocyte antigen (HLA) typing revealed A24 positivity, suggesting this molecule was interacting with CD8(+) T lymphocytes. It was suggested that immunological disharmony and autoimmunity would play a pivotal role in the development of HP under genetic background of HLA-A24, and HP would be one feature of multiple organ involvement in ANCA-associated diseases.

Primary biliary cirrhosis (PBC)-CREST overlap syndrome with coexistence of Sjögren's syndrome and thyroid dysfunction.

Calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia (CREST) syndrome, a limited form of systemic sclerosis, is sometimes complicated by primary biliary cirrhosis (PBC). A 52- and 61-year-old Japanese woman with PBC-CREST overlap syndrome accompanied by Sjögren's syndrome, and Hashimoto's thyroiditis, and Graves' disease, respectively, are reported. They had suffered from Raynaud's phenomena, sclerodactyly, morning stiffness, arthralgia, and sicca symptoms during these several years. They exhibited an increased level of alkaline phosphatase, gamma-glutamyl transpeptidase, positive antibodies against mitochondria and centromere, and hyperglobulinemia without any cholestatic symptoms. Histological findings from liver biopsy specimens were consistent with those of PBC. Clinically, they were diagnosed as both asymptomatic PBC and incomplete CREST syndrome. Their human leukocyte antigen typing showed both DR4 and DR8 positive. The association of the four autoimmune conditions is clinically and etiologically important. Although a combination of these diseases is rare, it is of importance to keep in mind that various autoimmune diseases could occur simultaneously. Of critical importance is that an active diagnostic attitude towards them is admirable, and that early diagnosis and therapy are needed.

A study of ten Japanese patients with seronegative spondylarthropathy: a tentative proposal.

We reviewed ten patients with seronegative spondylarthropathy (SNSA), who all fulfilled the European Spondylarthropathy Study Group criteria for spondylarthropathy (SpA); seven patients also met the Amor criteria for SpA. Seronegative spondylarthropathy was not a uniform syndrome but rather a wide spectrum of complex disease with characteristics of sacroiliitis and enthesopathy. The most frequent symptom at diagnosis of SNSA was inflammatory low back pain, followed by asymmetric oligoarthralgia and Achilles tendonitis and/or plantar fasciitis. Systemic complications were revealed as eye and skin involvement. Imaging methods including pelvic radiography, scintigraphy, and computed tomography scanning were useful in detecting spondylarthropathic changes, which were characteristic of SNSA. Human leukocyte antigen (HLA) typing showed various patterns among patients, in which HLA-B27 was positive in three patients with ankylosing spondylitis. HLA-B51, which is a well-known genetic factor associated with Behçet's disease (BD), was positive in two patients who were apparently distinct from BD. Two patients with palmoplantar pustulosis showed symptoms and signs characteristic of SNSA. Although we have few SNSA patients in the present study, we would like to propose that HLA-B51 positive SpA would be considered as a subset of SNSA, and that pustulotic SpA also would be classified as a member of SNSA. This led us to suggest the possibility to change the concept of SNSA proposed by Moll et al. The optimal treatment remains to be defined, but sulfasalazine was effectively used with almost all patients in combination with nonsteroidal anti-inflammatory drugs.

Gustatory sweating due to autonomic neuropathy in a patient with amyloidosis secondary to rheumatoid arthritis.

Abstract Autonomic neuropathy, although often reported to occur in patients with AL (amyloid of light chain of immunoglobulin) amyloidosis, is extremely rare in AA (amyloid A) amyloidosis. We describe a patient with AA amyloidosis secondary to rheumatoid arthritis (RA) in whom autonomic neuropathy resulted in gustatory sweating during the end stage of RA. We discuss the importance of gustatory sweating as a characteristic sign of autonomic nervous system dysfunction in AA amyloidosis secondary to RA, and stress the availability of cardiovascular autonomic tests as an indicator of autonomic neuropathy in not only AL amyloidosis but also AA amyloidosis.

Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis.

Secondary amyloid A (AA) amyloidosis is an uncommon yet important complication of rheumatoid arthritis (RA). It is one of the most relentless of the extra-articular features of RA, and suitable treatments have not yet been found. We studied the efficacy of cyclophosphamide (CYC) combined with prednisolone (PSL) in amyloidotic patients who had serum amyloid A (SAA) 1.3 genotype, which is a risk factor for secondary amyloidosis in Japanese RA patients. Fifteen RA patients who were SAA1.3 homo- and heterozygotes with biopsy-confirmed AA amyloidosis were treated with a combination of CYC and PSL. Laboratory variables of C-reactive protein (CRP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), serum albumin (Alb), serum creatinine (Cre) and Lansbury's index were carried out by statistical analysis of changes between before and during the medication. According to the Mann-Whitney rank test, CRP, RF, ESR, Alb and Cre levels improved significantly with the combination treatment (p<0.05). Also, paired t-tests showed significance in Lansbury's index between before and during the medication (p=0.007). CYC combined with PSL ameliorated not only laboratory markers but also clinical rheumatoid activity in patients with amyloidosis secondary to RA, whose genotypes were SAA1.3 homo- and heterozygous. CRP, ESR, RF, Alb and Cre will be surrogate markers of therapeutic efficacy. The combination of CYC and PSL appears to be beneficial for Japanese RA patients who are SAA1.3 homo- and heterozygous carriers, associated with secondary AA amyloidosis.

Polyarteritis nodosa limited to calf muscles: a case report and review of the literature.

We describe an unusual case of a 38-year-old woman with a localised form of polyarteritis nodosa (PAN) manifested by acute onset of severe calf pain. Magnetic resonance imaging of the lower legs showed abnormal signal intensity of the outer calves muscle. Biopsies of the gastrocnemius revealed an acute necrotising arteritis with marked non-specific fasciitis. The diseased muscle improved with corticosteroid administration alone. The fascial involvement likely contributed to the severity of the clinical features of PAN, which may be related to a previous hepatitis B virus infection.