Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

Abatacept may be effective and safe in patients with amyloid A amyloidosis secondary to rheumatoid arthritis.

OBJECTIVES: To examine the efficacy and safety of abatacept (ABT) in patients with amyloid A (AA) amyloidosis secondary to rheumatoid arthritis (RA), and to speculate about the immunologic association of ABT with AA amyloid deposit regression. METHODS: We administered ABT to 70- and 65-year-old Japanese women with RA and AA amyloidosis. We quantified serum cytokine concentrations and analysed regulatory T lymphocytes (Treg cells) via flow cytometry. We also studied AA amyloid deposits via histopathology and immunohistochemistry. RESULTS: ABT improved rheumatoid inflammation and AA amyloidosis, one case showing clinical remission and the other demonstrating incomplete recovery of nephrosis but stable kidney function. Serum levels of interleukin-6 and tumour necrosis factor α decreased to baseline in the first 6 months of treatment, but serum interleukin-2 concentrations did not change. CD4+CD25++FoxP3+ Treg cells gated on T lymphocytes and CD4+ T lymphocytes decreased to baseline in the first 3 treatment months. One case showed complete regression of AA amyloid fibrils in serial upper gastrointestinal biopsies, but the other case still had AA amyloid deposits despite ABT-induced normalised rheumatoid inflammation, with polymorphonuclear leukocytes and macrophages infiltrating tissues containing AA amyloid. CONCLUSIONS: ABT demonstrated efficacy and safety in AA amyloidosis secondary to RA and affected Treg cells and inflammatory cytokines. Because the gradual decrease in Treg cells population coincided with AA amyloid deposit regression during ABT therapy, AA amyloid fibril turnover in these patients may involve an immunologic mechanism. Phagocytes seemed to have an important role in AA amyloid fibril regression, which suggests an immunologic interaction.

Amyloid A amyloidosis in a Japanese patient with familial Mediterranean fever associated with homozygosity for the pyrin variant M694I/M694I.

Familial Mediterranean fever (FMF) is an autoinflammatory disease common in eastern Mediterranean populations. The most severe complication is the development of secondary amyloid A (AA) amyloidosis. A 51-year-old Japanese male who had been suffering from periodic fever since in his twenties was referred to our hospital for proteinuria. Histological findings from renal biopsy revealed the deposition of AA amyloid fibrils, suggesting that renal dysfunction was due to AA amyloidosis. Gene analysis of the patient and his mother showed that both were homozygous for the M694I mutation in the MEFV gene. His mother was also a carrier of the SAA1.3 allele, which is not only a univariate predictor of survival but also a risk factor for the association of AA amyloidosis with rheumatoid arthritis in Japanese patients, and the SAA1-13T allele in the 13T/C polymorphism on the 5'-flanking region of the SAA1 gene. The patient was also a carrier of the SAA-13T allele. Colchicine resulted in not only an amelioration of the acute febrile attacks of FMF inflammation, but also an improvement in kidney dysfunction due to AA amyloidosis.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Rheumatoid arthritis caused by non-tuberculous mycobacteria infection.

A 72-year-old Japanese woman had right digital flexor tenosynovitis with a non-tuberculous mycobacteria (NTM) infection, which was identified as Mycobacterium marinum in culture. She had been treated at another hospital with clarithromycin, rifampicin, and ethambutol for the non-tuberculous tenosynovitis. However, the swelling of her right hand worsened, and 5 months later, her left hand swelled and she exhibited symmetrical arthritis. Blood tests detected elevated serum C-reactive protein and rheumatoid factor positivity. Although rheumatoid arthritis (RA) was suspected and corticosteroid treatment was started, she came to our hospital because of the insufficient treatment effect. Musculoskeletal ultrasonography showed intra-articular and peritendinous power Doppler signal-positive symmetrical synovitis. A contrast-enhanced magnetic resonance imaging (MRI) evaluation of the left hand without NTM tenosynovitis revealed findings of inflammatory synovitis accompanied by bone marrow oedema. We diagnosed RA and started treatment with weekly low-dose methotrexate pulses and 2 weeks of tocilizumab administration; her symptoms then disappeared within 2 months. This is a rare case of RA manifested with NTM-associated arthritis.

An autopsy case of necrotizing fasciitis with rapidly progressive purpura caused by hemolytic streptococcal infection in a patient with rheumatoid arthritis.

A 77-year-old woman with rheumatoid arthritis was admitted as an emergency because of pain in the right leg with purpura. She was diagnosed with severe cellulitis and sepsis and started on intravenous antibiotics; however, the lesion rapidly extended to the proximal thigh and she died only 38 h after the onset of the first symptom. Autopsy and tissue culture revealed necrotizing fasciitis caused by Streptococcus dysgalactiae subspecies equisimilis. Physicians should consider that necrotizing fasciitis may be present when soft-tissue disorder is suspected in patients receiving corticosteroid therapy, which is associated with tissue fragility and immunosuppression.

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study.

ABSTRACT: We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.

Diffuse chronic leptomeningitis with seropositive rheumatoid arthritis: report of a case successfully treated as rheumatoid leptomeningitis.

A case of biopsy-confirmed chronic leptomeningitis complicating rheumatoid arthritis in a 53-year old female is reported. Her symptoms included weight loss, severe depression, and pyrexia. Magnetic resonance imaging was useful in diagnosis. Intravenous methylprednisolone was prescribed (1 g/day for 3 days), followed by prednisolone (initial dose of 30 mg daily), and this treatment was effective. Her IgG-index, serum levels of soluble interleukin-2 receptor and ferritin, and cerebrospinal level of interleukin-6 paralleled her clinical course.

Systemic Lupus Erythematosus-associated Acute Acalculous Cholecystitis Successfully Treated by a Corticosteroid Combined with Azathioprine.

A 69-year-old Japanese woman was transferred to our hospital due to pancytopenia with a fever. She had Murphy's sign, and computed tomography showed pleural effusion and a swollen gallbladder without gallstones. We diagnosed her with systemic lupus erythematosus (SLE)-associated acute acalculous cholecystitis (AAC). Partly because her clinical and laboratory findings were not serious enough to warrant immediate surgical intervention, and partly because her poor general condition made her ineligible for surgery, surgical therapy was not selected. Corticosteroid therapy was performed with azathioprine, and the swelling in her gallbladder improved. As a conservative therapy for SLE-associated AAC, corticosteroid therapy combined with azathioprine might be beneficial.

Dystrophic calcinosis with both a huge calcified mass in the cervical spine and calcification in the chest wall in a patient with rheumatoid overlap syndrome.

Dystrophic calcinosis in soft tissue occurs in damaged or devitalized tissues in the presence of normal calcium and phosphorous metabolism. It is often noted in subcutaneous tissues in patients with collagen vascular diseases and may involve a relatively localized area or be widespread. A 74-year-old Japanese woman with an overlap of rheumatoid arthritis, Sjögren's syndrome, and systemic sclerosis developed a huge tumor-like mass at the atlanto-axial vertebral joint region that caused severe cervical pain and difficulty in activities of daily living. She also had subcutaneous dystrophic calcification in the soft tissue of the chest wall. Calcinosis associated with systemic sclerosis is a well-recognized phenomenon, but a destructive paraspinal tumor in the cervical spine associated with overlap syndrome is extremely unique. Because calcinosis in spinal locations can be complicated by neurological involvement, patients with progressive symptoms may require surgical intervention. Surgical resection and biological therapy improved this patient's life and activities of daily living. Calcinosis is common in the conditions reviewed here, and different agents have been used for treatment. However, calcinosis management is poorly organized and lacks an accepted classification, systematic studies, and clinical therapeutic trials. The association of calcinosis and collagen vascular diseases is clinically and etiologically important. Although a combination of calcinosis and rheumatoid overlap syndrome is rare, various collagen vascular diseases may occur simultaneously. A perceptive diagnostic approach toward these diseases is critical, and early diagnosis and treatment are needed to prevent dystrophic calcinosis.

Case of granulomatosis with polyangiitis (Wegener's granulomatosis) manifested with asymptomatic intracerebral hemorrhage.

A 46-year-old man, who had had sinusitis, developed bilateral omalgia, petechiae on his lower extremities and a congested right eye. A blood test detected elevated serum C-reactive protein level. Computed tomography incidentally found an acute lesion of thalamic hemorrhage without neurological symptoms and no specific therapy was given at the time. Thereafter, he developed vertigo, vomiting and pneumonia for which antibiotics were ineffective. He was referred and admitted to our hospital. Further, aural and renal lesions, and presence of serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) confirmed his diagnosis of granulomatosis with polyangiitis (Wegener's) (GPA). With corticosteroid and cyclophosphamide therapy, his symptoms disappeared in two months along with faded PR3-ANCA. Afterward he showed neither new cerebral lesion nor symptom. This is a rare case of GPA manifested with asymptomatic intracerebral hemorrhage. It should be noted that GPA could cause various manifestations in central nervous system such as a fatal or an asymptomatic hemorrhagic lesion, which might respond to immunosuppressive therapy.

[Case of immunosuppressant-resistant amyopathic dermatomyositis with rapidly progressive interstitial pneumonia ameliorated after resection of gastric cancer].

A 59-year old woman had been suffering from myalgia, eruption and dyspnea on effort for a month. She was referred to our hospital because her symptoms were not improved by antibiotic therapy at a clinic. At first presentation she showed cutaneous manifestations including heliotrope eyelids and mechanic's hands, slightly elevated serum creatine kinase (CK), elevated serum C-reactive protein level, and interstitial pneumonia (IP), which led to a diagnosis as dermatomyositis. After admission to our hospital, her hypoxia due to IP progressed despite disappeared myalgia and normalized serum CK level. Intravenous steroid pulse therapy followed by oral cyclosporine and intravenous cyclophosphamide pulse therapy was not effective for the IP for more than a month. Gastroscopy revealed superficial depressed (0-IIc) type early gastric cancer. However, it was out of indication for endoscopic mucosal resection because of the histopathologic type (signet ring cell carcinoma) and possible submucosal invasion. In addition to those immunosuppressive therapies, proximal gastrectomy with total intravenous anesthesia was performed. One month after the operation, improvement of IP as well as cutaneous manifestations was confirmed by respiratory function test, pulmonary computed tomography, and discontinuance of oxygen inhalation. We conclude that this was a case of clinically amyopathic dermatomyositis with rapidly progressive IP and gastric cancer, which was ameliorated by a combination of medication (steroid, cyclosporine, and cyclophosphamide) and surgery (gastrectomy for early gastric cancer).

Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope.

INTRODUCTION: Interstitial Lung Disease (ILD) is frequently associated with Rheumatoid Arthritis (RA) as one of extra-articular manifestations. Many studies for Human Leukocyte Antigen (HLA) allelic association with RA have been reported, but few have been validated in an RA subpopulation with ILD. In this study, we investigated the association of HLA class II alleles with ILD in RA. METHODS: An association study was conducted on HLA-DRB1, DQB1, and DPB1 in 450 Japanese RA patients that were or were not diagnosed with ILD, based on the findings of computed tomography images of the chest. RESULTS: Unexpectedly, HLA-DRB1*04 (corrected P [Pc] = 0.0054, odds ratio [OR] 0.57), shared epitope (SE) (P = 0.0055, OR 0.66) and DQB1*04 (Pc = 0.0036, OR 0.57) were associated with significantly decreased risk of ILD. In contrast, DRB1*16 (Pc = 0.0372, OR 15.21), DR2 serological group (DRB1*15 and *16 alleles) (P = 0.0020, OR 1.75) and DQB1*06 (Pc = 0.0333, OR 1.57, respectively) were significantly associated with risk of ILD. CONCLUSION: HLA-DRB1 SE was associated with reduced, while DR2 serological group (DRB1*15 and *16) with increased, risk for ILD in Japanese patients with RA.