Clinical Observations of Osteoporosis in Japanese Patients with Rheumatoid Arthritis

Osteoporosis is the one of the major adverse outcomes in patients with rheumatoid arthritis (RA). Recently, we and others have been reported many clinical observations related to osteoporosis in Japanese RA patients. In this article, I reviewed these findings. Japanese patients with RA have a two-fold risk of fractures compared with those without RA. Among the fractures in Japanese RA patients, three quarters of the fractures were non-vertebral fractures. The incidence of non-vertebral fractures did not change, despite an improvement in RA disease activity. Older age, female gender, history of fractures, history of total knee replacements, disease activity scores in 28 joints (DAS28), health assessment questionnaire disability index (HAQ-DI), low bone mineral density, glucocorticoid dose, and vitamin D deficiency were significantly associated with fractures. Older age, high body mass index (BMI), HAQ-DI, and polypharmacy were significantly associated with falls. BMI (both overweight and underweight), DAS28, and HAQ-DI were significantly associated with frailty. Half and three quarters of Japanese men and women with RA had vitamin D deficiency, respectively. The incidence of osteonecrosis of the jaw may be higher in Japanese RA patients than those without RA. Undertreatment of osteoporosis appears to exist in Japanese patients with RA.

Avacopan, a Selective C5a Receptor Antagonist, for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Avacopan, an orally administered C5a receptor (C5aR) antagonist, has been approved for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan and the United States. In ADVOCATE Phase III clinical trial, patients with active MPA or GPA received either 30 mg avacopan twice daily or prednisone on a tapering schedule in combination with rituximab or cyclophosphamide (followed by azathioprine). The trial met its two primary endpoints: avacopan showed non-inferiority to prednisone for achieving remission at week 26 (avacopan, 72.3%; prednisone, 70.1%; p < 0.001 for non-inferiority and p = 0.24 for superiority) and superiority for maintaining remission at week 52 (65.7% for avacopan, 54.9% prednisone, p < 0.001 for non-inferiority and p = 0.007 for superiority). Of several key secondary endpoints tested, the glucocorticoid toxicity index (GTI)-cumulative worsening score and GTI-aggregate improvement score were significantly lower in the avacopan group than in the prednisone group at both weeks 26 and 52. Serious adverse events related and unrelated to the worsening vasculitis were reported at 10.2% and 37.3% in the avacopan group and at 14.0% and 39.0% in the prednisone group, respectively. Avacopan has set the stage for the semi-glucocorticoid-free or glucocorticoid-free treatment of MPA and GPA.

Effective Therapy of Tocilizumab on Systemic Juvenile Idiopathic Arthritis Associated Refractory Macrophage Activation Syndrome

Objectives To evaluate the safety and efficacy of tocilizumab (TCZ) on refractory macrophage activation syndrome (rMAS) associated with systemic juvenile idiopathic arthritis (sJIA-rMAS). Methods We retrospectively reviewed the charts of 14 patients diagnosed with sJIA-rMAS, who were treated with TCZ after failing conventional therapies at three hospital centers from Jan 2016 to Dec 2020. Demographic, clinical, and laboratory characteristics were recorded at the onset of MAS, before TCZ (pre-TCZ) and 14 days after TCZ (post-TCZ). Results The clinical manifestation of sJIA-rMAS included fever (100%), skin rashes (35.7%), lymphadenomegaly (42.9%), hepatomegaly (57.1%), splenomegaly (7.1%), gastrointestinal symptoms (28.6%), arthritis (14.3%), myalgia (28.6%) and polyserositis (14.3%). After TCZ treatment, fever (100%, 14/14), gastrointestinal symptoms (100%, 4/4) and myalgia (100%, 4/4) were significantly improved after one week (p< 0.05). Skin rashes, lymphadenomegaly and arthritis also improved in many patients but these parameters did not reach statistical significance. In post-TCZ group, decreases in levels of c-reactive protein, erythrocyte sedimentation rate and serum ferritin of sJIA-rMAS were observed compared with pre-TCZ (p< 0.05). Although not statistically significant, post-TCZ group showed normalization of white blood cell, platelet count, alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase and triglyceride levels compared with pre-TCZ. No disease relapse or fatality was recorded during the follow-up (25 months, range 3–60 months). Conclusions TCZ is safe and effective for the treatment of sJIA-rMAS after failure of conventional therapies.

SAPHO Syndrome and Pustulotic Arthro-Osteitis (PAO)

ABSTRACTS Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare inflammatory osteo-articular disorder, which encompassed many diseases, including pustulotic arthro-osteitis (PAO). Bone and joint manifestations, including osteitis, synovitis and hyperostosis, are the hallmark of the SAPHO syndrome and affect a variety of regions of the body. Recent GRAPPA survey indicated that more than 80 percent of cases of SAPHO syndrome in Japan were thought to be PAO, originally proposed by Sonozaki et al. in 1981, whereas severe acne was the most commonly reported skin ailment amongst participants with SAPHO syndrome in Israel. SAPHO syndrome is a rare disease and adequate data regarding its prevalence remains unavailable, whereas prevalence of PPP was reported to be 0.12 % in Japan and 10-30% of patients with PPP had PAO. SAPHO syndrome and PAO are predominantly found in patients in the third through fifth decades of life, and a female predominance are seen in both groups. The diagnosis of SAPHO syndrome/PAO is typically made by a rheumatologist or dermatologist. Identification of a variety of the clinical, radiological, and laboratory features outlined, as well as diagnostic criteria, are used to make the diagnosis. Goals for treating patients with SAPHO syndrome/PAO seek to maximize health-related quality of life by improving skin and articular symptoms, preventing structural changes and destruction, and normalizing physical function and social participation. Finally, we review the non-pharmacological (ie: smoking cessation and controlling focal infections) and pharmacological managements including NSAIDs, bisphosphonates, cs DMARDs, bDMARDs, and other treatments for SAPHO syndrome/PAO.

Radiographic Factors Associated with Painful Callosities After Forefoot Surgery in Patients with Rheumatoid Arthritis

ABSTRACT Objectives Operative procedures for rheumatoid forefoot deformities have gradually changed from arthrodesis or resection arthroplasty to joint-preserving surgery. Though joint-preserving arthroplasty has yielded good outcomes, painful plantar callosities may occur postoperatively. This study aimed to reveal the radiographic factors associated with painful callosities after joint-preserving surgery for forefoot deformities in patients with rheumatoid arthritis (RA). Methods We retrospectively evaluated 166 feet in 133 patients with RA who underwent forefoot joint-preserving arthroplasty, including proximal rotational closing-wedge osteotomies of the first metatarsal, between January 2012 and December 2015. Logistic regression analysis was performed with the objective variable set as the presence/absence of painful plantar callosities at the final observation and the explanatory variables set as several radiographic factors including postoperative relative first metatarsal length (RML), amount of dorsal dislocation of the fifth metatarsal (5DD), and arc failure of the lesser toes. Results At the final follow-up, forty-two of the 166 feet (25.3%) had painful callosities under the metatarsal heads postoperatively. Logistic regression analysis showed that the RML, 5DD, and lesser toes’ arc failure were significantly associated with painful callosities. Conclusions We identified RML, 5DD, and arc failure of the lesser toes were associated with painful plantar callosities after the surgery.

Predictors of Infliximab Refractory Intestinal Behçet’s Syndrome: A Retrospective Cohort Study from the Shanghai Behçet’s Syndrome Database

ABSTRACT Objectives This retrospective cohort study aimed to find out predictors and early biomarkers of Infliximab (IFX) refractory Intestinal Behçet’s Syndrome (intestinal BS). Methods We collected the baseline clinical characteristics, laboratory parameters and concomitant therapies of intestinal BS patients treated by IFX from the Shanghai Behçet’s syndrome database. After 1-year IFX therapy, intestinal BS patients with non-mucosal healing (NMH, intestinal ulcers detected by colonoscopy) and/or no clinical remission [NCR, scores of the disease activity index for intestinal Behçet’s disease (DAIBD) ≥ 20] was defined as IFX refractory intestinal BS. Multivariate logistic regression analysis was performed to evaluate the predictors for NMH and NCR in IFX refractory intestinal BS. Results In 85 intestinal BS patients, NMH was identified in 29 (34.12%) patients, and NCR was confirmed in 20 (23.53%) patients. ESR (≥ 24mm/h) and fT3 (≤ 3.3pmol/L) were the independent risk factors of NMH in IFX refractory intestinal BS. Drinking alcohol and the fT3/fT4 ratio (≤ 0.24) were independent risk factors, and thalidomide was an independent protective factor, for NCR in intestinal BS patients treated by IFX. Conclusion This study may be applicable for adjusting the therapeutic strategy and sidestepping unnecessary exposure to IFX in intestinal BS patients. Routine assessments of ESR, fT3 and fT3/fT4 ratio are helpful to identify high-risk individuals of IFX refractory intestinal BS. Thalidomide is suggested to be a concomitant therapy with IFX for intestinal BS patients.

Predictive Factors for Achievement of Treatment Goals in Patients with Postmenopausal Osteoporosis Treated with Denosumab

Objectives To investigate efficacy of long-term treatment with denosumab and predictive factors for achievement of treatment goals in patients with postmenopausal osteoporosis (PMO). Methods We enrolled 111 PMO patients who had T-scores ≤ -2.5 either at the lumbar spine (L-) or femoral neck (FN-), who had never been treated for osteoporosis, and who could be followed for at least 3 years. We first evaluated changes in bone mineral density (BMD) for up to 7 years. We next defined the treatment goal as the achievement of a T-score > -2.5 at month 36 and performed multivariate analysis to identify predictive factors for achievement of the goal. Results L- and FN-BMD increased yearly for 7 years. Among 87 patients with baseline L-T-scores ≤ -2.5, better baseline L-T-scores predicted achievement of L-T-scores > -2.5 at month 36. The cut-off value for baseline L-T-score was -3.4. Among 76 patients with baseline FN-T-scores ≤ -2.5, better baseline FN-T-scores predicted achievement of FN-T-scores > -2.5 at month 36. The cut-off value for baseline FN-T-scores was -2.8. Conclusions Long-term treatment with denosumab was effective in PMO patients. As better baseline T-score predicted achievement of T-scores > -2.5, early initiation of treatment will contribute to better outcome.

Anti-Ro/SS-A Antibody is Associated with Worse Pulmonary Outcome and Reduced Overall Survival in Systemic Sclerosis

ABSTRACT Objective We sought to determine the association of anti-Ro/SS-A antibody with organ involvement and disease outcome, in patients with systemic sclerosis (SSc). Methods A retrospective, long-term study of a cohort of incident patients diagnosed with SSc, and continuously followed at our rheumatology clinic during 1990-2018. Results Included were 105 patients with known anti-Ro/SS-A antibody status, 92.4% female, mean age at diagnosis 52.0±15.6 years, and median follow-up 10 years; 64% were diagnosed with limited cutaneous SSc, 18% with diffuse cutaneous SSc, and 18% had SSc siné scleroderma or undetermined disease type. Anti-Ro/SS-A antibody tested positive in 21% of patients. In univariate analysis, anti-Ro/SS-A antibody-positivity was significantly associated with SSc overlap with Sjogren’s syndrome (p <0.001). Pulmonary function tests (PFT) deterioration at last encounter was significantly associated with anti-Ro/SS-A antibody-positivity. In multivariate regression for anti-Ro/SS-A antibody-positive SSc patients and disease outcome (adjusted for age>50 years, smoking, and baseline predicted forced vital capacity (pFVC) < 80%), positive anti-Ro/SS-A antibody was significantly associated with higher all-cause mortality rate (HR 5.17, CI 95% 1.18-22.67, p=0.029), and greater deterioration of pFVC defined as decrement of last available pFVC compared to first available pFVC of ≥10% (HR 3.65, CI 95% 1.07-12.38, p=0.038). Conclusions Anti-Ro/SS-A antibody is an independent risk factor for worse pulmonary outcome and higher all-cause mortality in patients with SSc, independent of SSc clinical and/or serological subtype.

Factors Associated with Bone Erosion in Patients with Gout: A Dual-Energy Gemstone Spectral Imaging Computed Tomography Study

ABSTRACT Objective This study aimed to assess the factors influencing bone erosion in patients with gout using dual-energy gemstone spectral imaging CT. Methods We compared the clinical data, laboratory indices, and tissue urate levels at the monosodium urate (MSU)-bone interface measured by dual-energy gemstone spectral imaging computed tomography of 87 gout patients with (n=41) and without (n=46) bone erosion. Logistic regression analysis was used to investigate the risk factors associated with bone erosion. Results In total, 47.1% of patients with gout had bone erosion. The disease duration, serum uric acid, tissue urate levels, and the presence of tophi were significantly higher (p<0.05) in gout patients with bone erosion than in those without bone erosion. Longer disease duration (OR=1.11, 95% CI: 1.00–1.24, p<0.05) and increased tissue urate levels (OR=1.01, 95% CI: 1.00–1.02, p<0.05) were independently associated with bone erosion. Tissue urate levels at the MSU-bone interface were correlated with the presence of tophi (r=0.62, p<0.001), bone erosion (r=0.51, p<0.001), renal calculus (r=0.24, p=0.03), and serum uric acid levels (r=0.23, p=0.03). Conclusion This study found that longer disease duration and elevated tissue urate concentrations at the MSU-bone interface were associated with bone erosion in patients with gout.

Long-Term Safety and Efficacy of Belimumab in Japanese Patients with SLE: a 7-Year Open-Label Continuation Study

Objectives Evaluate long-term safety, tolerability and efficacy of belimumab in Japanese patients with systemic lupus erythematosus (SLE). Methods This was a subgroup analysis of Japanese patients who completed studies BEL113750 or BEL112341 and were enrolled in a Phase 3, open-label extension study (BEL114333; NCT01597622). Eligible patients received intravenous belimumab 10 mg/kg every 28 days for ≤7 years. Primary endpoint: safety and tolerability. Secondary endpoints included SLE responder index (SRI)-4 response rate, SRI-4 components, severe SLE flare, use of corticosteroids/other SLE-related treatments. Analyses were based on observed data from first parent or current study belimumab dose through to study end. Results Of 71 Japanese patients enrolled, 69.0% completed the study. Overall, 98.6% patients had adverse events (AEs); 32.4% had serious AEs. The proportion of SRI-4 responders increased progressively (Year 1, Week 24: 40.9% [27/66]; Year 7, Week 48: 84.6% [11/13]) as did the proportion of SELENA-SLEDAI responders. The proportion of patients with no worsening in PGA (91.2−100.0%) and no new organ damage (92.6−100.0%) remained stable over time. Severe SLE flare was experienced by 11.3% (8/71) of patients. Corticosteroid and immunosuppressant use decreased over time. Conclusion : Favorable safety profile and treatment responses with belimumab were maintained for ≤7 years in Japanese patients with SLE.