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This study used data from a large-scale multicenter medical information database in Japan to estimate the incidence rate of herpes zoster (HZ) and to examine the relationship between hypertension, dyslipidemia, and diabetes mellitus (DM), and the risk of HZ among patients with rheumatoid arthritis (RA). The research dataset consisted of 221,196 records of potential target patients with RA extracted between April 1, 2008 and August 31, 2017 from the Medical Data Vision database. To assess the association between hypertension, dyslipidemia, and DM and the risk of HZ, a case–control study was set up. Records of 101,498 study subjects met the inclusion criteria. During the observation period, 2566 patients developed HZ and the overall incidence rate was 5.2 (95% confidence interval: 5.0–5.4 per 1000 patient-years). Hypertension, dyslipidemia, and DM were significantly associated with an increased risk of HZ after adjustment for sex, age, hospital size, and use of anti-rheumatic drugs. When mutual adjustment was made for hypertension, dyslipidemia, and DM, the positive associations between hypertension and dyslipidemia and the risk of HZ remained significant; however, the positive association with DM completely disappeared. RA patients with hypertension or dyslipidemia may be at higher risk of HZ. Supplementary Information The online version contains supplementary material available at 10.1007/s00296-021-04889-1.

Background To analyse the subsequent clinical course of patients with rheumatoid arthritis (RA) who either continued or discontinued biologic agents after hospitalization for infections. Methods We retrospectively reviewed the clinical records of 230 RA patients with 307 hospitalizations for infections under biologic therapy between September 2008 and May 2014 in 15 institutions for up to 18 months after discharge. The risks of RA flares and subsequent hospitalizations for infections from 61 days to 18 months after discharge were evaluated. Results Survival analyses indicated that patients who continued biologic therapy had a significantly lower risk of RA flares (31.4% vs. 60.6%, P P = 0.37). Multivariate analysis showed that discontinuation of biologic therapy, diabetes, and a history of hospitalization for infection under biologic therapy were associated with RA flares. Oral steroid therapy equivalent to prednisolone 5 mg/day or more and chronic renal dysfunction were independent risk factors for subsequent hospitalizations for infections. Conclusions Discontinuation of biologic therapy after hospitalization for infections may result in RA flares. Continuation of biologic therapy is preferable, particularly in patients without immunodeficiency.

ObjectivesThe aim of this study is to determine whether the ‘programmed’ infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year.MethodsIn this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106.ResultsA total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI −6.6% to 11.0%; p=0.631). Baseline SDAI ConclusionProgrammed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

Metatarsus primus elevatus, described as dorsal elevation of the first metatarsal in relation to the lesser metatarsals, is rarely observed in patients with rheumatoid arthritis. We describe a pati...

Background The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. Methods HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. Results Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. Conclusions Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.

Background The difference between total and healthy life expectancies were 12.3 and 8.8 years for women and men respectively in 2016, in Japan. Rheumatoid arthritis (RA) not only reduces daily living activities due to joint symptoms but also deteriorates the life prognosis due to systemic inflammation. That is, patients with RA are short for both total and healthy life expectancy. In recent years, the need for rheumatologist to provide specialty medical care to elderly patients with RA has been expanding. However, some elderly patients drop out of specialty treatment and care. To date, there are little information concerning background of patients who drop out. Objectives To investigate reasons and characteristics of elderly RA patients who drop out from rheumatology specialty medical care. Methods Of RA patients who had been visited our rheumatology specialty facility in 2016, we defined as drop-out when the patients did not return to the hospital in 2017. We surveyed age, gender, disease activity, and reason for drop-out retrospectively from medical records and questionnaires. Results Of 2,092 patients with RA who visited to our department, 156 patients (7.5%, 95% confidential interval: 6.4 – 8.6%) dropped out. Among drop-out patients, 101 patients were older than 65. 37 patients (37%) dropped out due to comorbidities including death (group C), 32 (32%) patients were introduced certified rheumatologists near the patients’ residences (group R). Twenty-two patients were due to unknown reasons, nine were due to remission, and one patient moved out to other area. Average age of both group C and R were eighty years old. Glucocorticoid user rate (C: 89%, R: 71%) and dose (C: 5.6 mg, R: 5.7 mg) were similar in the both two groups. Patients in group C showed less use of methotrexate (C: 19% vs R: 58%, P Conclusion Some elderly RA patients, especially may drop out from rheumatology specialty care due to comorbidities. Regional co-management should be constructed so that elderly patients could continue receiving RA specialized care. Disclosure of Interests None declared

Background Typical foot deformity patterns of patients with rheumatoid arthritis (RA) include hallux valgus, claw toes, splay foot, flat foot, and hindfoot valgus deformities. However, some patients show deformities different from a typical pattern, including metatarsus primus elevatus, described as dorsal elevation of the first metatarsal in relation to the lesser metatarsals, as we reported previously. In the report, we speculated that metatarsus primus elevatus might be associated with calcaneal inclination and hindfoot varus alignment. However, there are no studies on the association of hindfoot alignment with metatarsus primus elevatus in patients with RA. Objectives To elucidate the impact of hindfoot coronal/sagittal alignment on metatarsus primus elevatus in patients with RA. Methods A retrospective study was performed of standing anteroposterior and lateral radiographs of 81 feet in 53 patients who underwent surgical treatment for metatarsalgia in our hospital. The distance between the dorsal cortical bones of the first and second metatarsals (MPE) was measured on the lateral radiograph for the degree of metatarsus primus elevatus. Using a two-dimensional coordinate system on the lateral radiographic image where lines along the calcaneus tuberosity were defined as X and Y axes, ten anatomic points of the foot were measured. Calcaneal pitch, talar declination angle, and naviculocuboid (N/C) overlap ratio were measured for assessment of hindfoot sagittal and coronal alignment, respectively. We assessed the hallux valgus angle (HVA), the inter metatarsal angle between first and 2nd metatarsals (M1M2A), and the intermetatarsal angle between first and 5th metatarsals (M1M5A) for axial foot alignment. The correlations of MPE with other radiographic angular and coordinate data were statistically assessed using Spearman rank correlation coefficient. Results Median MPE was 1.7 mm (interquartile range: 0–5.2 mm). The first metatarsal head, first metatarsal-cuneiform and posterior talocalcaneal joint were shifted dorsally (r=0.70, p Conclusion In patients with RA, the hindfoot joints shifted dorsally in metatarsus primus elevatus. Moreover, hindfoot varus alignment and high-arched foot affect metatarsus primus elevatus. The results of the present study suggest the importance of evaluating hindfoot alignment when determining surgical treatment procedures for rheumatoid foot deformities. Disclosure of Interests None declared

BackgroundAlthough the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial.ObjectivesTo investigate the incidence and risk factors for HBV reactivation in patients with RD.MethodsWe performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded.ResultsAmong 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3–182 months; median, 66 months).ConclusionsThe incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

OBJECTIVE Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. METHODS In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), β-blockers, non-steroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ≥5 mEq/L. Univariate and multivariate analyses were performed. RESULTS The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR

A cumulative effect of the susceptibility genes with polymorphic alleles may be responsible for rheumatoid arthritis (RA). The objective of this study was to clarify whether susceptibility to RA is under the control of common allelic loci between two different RA models induced by extrinsic and intrinsic factors, collagen-induced arthritis (CIA) in DBA/1 mice and arthritis in MRL/Mp (MRL) mice associated with the Fas deficient mutant gene, Fas(lpr), respectively. CIA was examined in mice of parental DBA/1 and MRL, (MRL x DBA/1) F1 and (MRL x DBA/1) F2 progenies. In genome-wide screening of the severity in the F2 using microsatellite markers, significant linkage was observed on chromosomes 5 and 17 at map position of D5Mit259 and H-2, respectively, associated with DBA/1 alleles, while there was no loci associated with arthritis of MRL-Fas(lpr) mice previously identified. In a quantitative trait locus (QTL) analysis, the locus on chromosome 5 showed the highest peak at map position 35 cM (LOD score 6.0). This study may indicate that the arthritis induced by extrinsic and intrinsic factors is under the control of a different combination of susceptibility genes with common and different alleles, possibly simulating the genetic heterogeneity of RA.

Vascular cell adhesion molecule-1 (VCAM-1, CD106) is important in leukocyte trafficking and its increased expression is associated with a number of chronic inflammatory diseases, including rheumatoid arthritis (RA). A soluble form of VCAM-1 (sVCAM-1) is generated by shedding of the membrane-bound molecule. The concentration of sVCAM-1 is increased in the sera of RA patients, but its pathological role has not been elucidated. The effect of sVCAM-1 relative to protection or aggravation of disease on the development of spontaneous arthritis was examined in an animal model of RA, namely MRL-Fas(lpr) mice (which display a disease resembling human RA), by generation of sVCAM-1 transgenic MRL-Fas(lpr) mice. Transgenic MRL-Fas(lpr) mice that expressed sVCAM-1 had higher incidence and increased severity of arthritis associated with higher levels of serum IgG rheumatoid factor compared with non-transgenic MRL-Fas(lpr) mice. These results suggest that sVCAM-1 plays an arthritogenic role in the development of inflammatory arthritis in MRL-Fas(lpr) mice and may present an important target for therapeutic strategy of RA.

We report a case of neuropsychiatric systemic lupus erythematosus successfully treated with mycophenolate mofetil (MMF). The patient was a 40-year-old female who maintained with 7 mg of prednisolone plus 100 mg of azathioprine (AZ) per day. According to transient ischemic attack that occurred repeatedly and an elevated level of interleukin-6 (IL-6) in spinal fluid, she was diagnosed as having neuropsychiatric systemic lupus erythematosus (NPSLE). Initial increase in doses of prednisolone and AZ to 20 mg and 150 mg per day, respectively, was ineffective. After switching from AZ to MMF, her symptoms of NPSLE completely resolved with marked improvement of the IL-6 level in her spinal fluid, suggesting that MMF was effective.

We report a case of IgG4-related disease (IgG4-RD) with multiple ten-organ involvement. This case showed many clinical findings, such as bilateral swelling of salivary and lacrimal glands, autoimmune pancreatitis, interstitial nephritis, retroperitoneal fibrosis, periaortitis, systemic swelling of lymph nodes, pulmonary lesions, splenomegaly, and jejunal lesions. He was suspected as having SLE or malignant lymphoma but diagnosed as having IgG4-RD by the elevated serum IgG4 level and histological findings from kidney and lymph node. We report a case of IgG4-RD with multiple ten-organ involvement that was successfully treated with prednisolone therapy.

Rheumatoid arthritis (RA) is a systemic disorder characterized by synovial inflammation and subsequent destruction and deformity of synovial joints. The articular lesions start with synovitis, focal erosion of unmineralized cartilage, and then culminate in the destruction of subarticular bone by pannus tissue. Periarticular osteopenia and systemic osteoporosis follow as late complications of RA. Osteoclasts, specialized cells that resorb bone, play a central role in developing these osteolytic lesions. To elucidate the mechanism of osteoclastogenesis and bone destruction in autoimmune arthritis, we investigated the expression of RANK ligand (RANKL), RANK, and osteoprotegerin (OPG) mRNA in a mouse type II collagen-induced arthritis (CIA) model by in situ hybridization. The results indicated that most of the TRAP-positive mono- and multinucleated cells in the inflamed and proliferating synovium and in the pannus were RANK-positive authentic osteoclasts and their precursors. In the inflamed synovium and pannus of the mouse CIA model, synovial fibroblastic cells around these RANK-positive cells were strongly positive for RANKL. Moreover, RANKL-positive osteoblasts on the endosteal bone surface, at a distance from the affected synovial joints, increased significantly in the mouse CIA model prior to periarticular osteopenia and systemic osteoporosis. These data indicated that the RANKL-RANK system plays an important role for osteoclastogenesis in both local and systemic osteolytic lesions in autoimmune arthritis, and can therefore be a good target for therapeutic intervention.

RAを含むヒト膠原病と極めて類似した病態,病理を自然発症するMRL/Mp-lpr/lprマウスをモデルとして,その関節炎の発症を規定する遺伝子座を,膠原病を発症しないC3H/HeJ-lpr/lprマウスとのもどし交配系を用いてマッピングした.その結果,関節炎は複数の感受性および抵抗性遺伝子座に支配されていること,また,これらの感受性遺伝子座間に相加性および階層性が存在することが明らかとなった.しかもこれらは唾液腺炎,血管炎,腎炎の疾患感受性遺伝子座とは異なる領域にマップされ, RAが他の膠原病とは遺伝的に分離可能な遺伝子群により支配されている可能性が示唆された.これらはRAをポリジーン系疾患としてシミュレートする上で,また,膠原病の病像多様性の起源を説明する上でも重要な事実であると考えた.

Background Although the reactivation of hepatitis B virus (HBV) is recognized as a serious complication in patients with connective tissue disease (CTD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors of reactivation remain controversial. Objectives We performed a multicentre, observational, prospective study across 16 Japanese Red Cross hospitals to clarify the prevalence and pathophysiology of HBV reactivation in patients with CTD. We report the results of 2-year observations in patients with resolved HBV infection. Methods Patients with CTD, treated with a dose of ≥5 mg/day prednisolone, and/or synthetic or biological ISDs, with negative HBs antigen and positive anti HBs and/or HBc antibody (Ab), were enrolled. HBV-DNA (RT-PCR) and related data were registered regularly. Results Among 1040 patients, including 950 rheumatoid arthritis, HBV-DNA was detected in 32 patients (1.75/100 person-years), and >2.1 log copy/ml was observed in 9 cases (0.49/100 person-years) over 1–2 years of observation. None of the reactivated patients, including six treated with a nucleic acid analogue, showed overt hepatitis. Low HBs Ab titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in 3 patients with positive HBs Ab and negative HBc Ab. The risk of reactivation among the different types of ISDs was not statistically different. The intervals from the start of ISD to reactivation were longer than previous reports (4–157 months, average 58.9 months). Conclusions HBV reactivation with ISD was 1.75/100 person-years in CTD patients with resolved HBV infection. Overt hepatitis was observed in none of the reactivated patients, and low HBs antibody titres and advanced age were risk factors for reactivation. Patients with positive HBs Ab and negative HBc Ab are not free from the risk of reactivation of HBV. References B. J Hepatol 2012: 57. 167–185 Disclosure of Interest None declared

Objective To analyze the influence of the genetic background of an arthritis-prone strain of mice, MRL, on the spontaneous development of arthropathy in DBA/1 mice, which histopathologically resembles enthesopathy in humans, and to clarify the strain-specific gene loci and their interactions that confer susceptibility to arthropathy. Methods MRL, DBA/1, (MRL × DBA/1)F1, and (MRL × DBA/1)F2 intercross mice were prepared, and the severity and onset of arthropathy of the ankle joints in individual mice were quantified (0–3 and 0–5 scale, respectively). A genome-wide scan of 271 male F2 intercross mice with polymorphic microsatellite markers was performed. Results Only male DBA/1, (MRL × DBA/1)F1, and (MRL × DBA/1)F2 mice developed arthropathy. The macroscopic and histopathologic findings of arthropathy in the F2 mice were similar to those in the parental DBA/1 mice, but the onset was significantly earlier. In the quantitative trait locus analysis of male F2 mice, 1 susceptibility locus for both the severity and early onset of the disease in the region of an MRL allele, Amd1, was located at marker D10Mit259 (map position 40.0 cM), which was common to 1 of the sialadenitis susceptibility loci in MRL mice, Asm1. Another susceptibility locus for the severity and early onset of arthropathy in the region of a DBA allele, Amd2, was located at D3Mit46 (29.5 cM). These loci manifested an additive effect on the development of arthropathy. Conclusion Arthropathy in DBA/1 mice is under the control of an allelic combination of gene loci, one of which is common to the locus for sialadenitis in MRL/MpJ-lpr/lpr mice.

Objective To clarify the mode of inheritance and the genome origins of arthritis in a lupus-prone strain of mice, MRL/MpJ, bearing a Fas deletion mutant gene, lpr (MRL/lpr). Methods Using non–lupus-prone strains of mice, C3H/HeJ-lpr/lpr (C3H/lpr), (MRL/lpr × C3H/lpr)F1 intercross and MRL/lpr × (MRL/lpr × C3H/lpr)F1 backcross mice were prepared. Arthritis in individual mice was analyzed by histopathologic grading, and the genomic DNA of the backcross mice was examined by simple sequence-length polymorphism analysis to determine the polymorphic microsatellite markers highly associated with arthritis. Results Arthritis-susceptibility loci with significant linkage were mapped between D15Mit111 and D15Mit18 (map position 17.8–18.7 cM) on chromosome 15 and between D19Mit112 and D19Mit72 (map position 43.0–55.0) on chromosome 19 (logarithm of odds scores 3.5 and 4.3, respectively). Three other loci, one mapped to each of chromosomes 1, 2, and 7, showed suggestive linkage. Loci homozygous for MRL alleles on chromosomes 1 and 19 enhanced arthritis in both sexes, whereas other loci on chromosomes 2 and 15 selectively affected males. A locus homozygous for MRL alleles on chromosome 7 inhibited arthritis in both sexes. Three of these loci were found to originate from an LG/J strain and 1 from an AKR/J strain. Some combinations of these loci showed an additive effect in a hierarchical manner on the development of arthritis. Conclusion Arthritis in MRL/lpr mice is a complex pathologic manifestation resulting from the cumulative effect of multiple gene loci with an allelic combination derived from the original inbred strains.