The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study.

We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone ≥20 mg/day (age ≥ 18 years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1 µg/day (n = 33), alendronate 35 mg/week (n = 37), and alfacalcidol plus alendronate (n = 36). The primary endpoints were changes in lumbar spine bone density at 6 months of treatment and the frequency of bone fracture at 12 months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1 week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12 months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.

Vertebral fractures affect functional status in postmenopausal rheumatoid arthritis patients.

Functional disability is a major concern in patients with rheumatoid arthritis (RA). This retrospective study investigated the risk factors for vertebral fractures (VFs) in postmenopausal RA patients and determined the impact of VFs on functional status. Data from a cohort of 200 postmenopausal RA patients in a single hospital registry were analyzed. Demographic and clinical data, imaging data from spine radiographs, and bone mineral density (BMD) data were collected from the patients at baseline and at the final visit (a mean of 2.9 years after the first visit). Risk factors for incident VFs and their impact on the modified health assessment questionnaire (mHAQ) were analyzed. Twenty-eight patients (14%) developed new VFs (NVFs). Logistic regression analysis adjusted for age, BMI, and disease duration revealed that daily dose of prednisolone, femoral neck BMD, use of active vitamin D3, and use of a bisphosphonate at baseline were factors associated with NVF, with odds ratios (95% confidence interval) of 1.27 (1.05-1.54), 0.94 (0.91-0.97), 0.34 (0.13-0.89), and 0.31 (0.12-0.82), respectively. Patients with NVF exhibited worse mHAQ scores and a greater increase in mHAQ scores from baseline compared with those without NVF. In conclusion, incident VFs were associated with reduced functional status in postmenopausal patients with RA. It is important to prevent VFs to maintain the functional status of RA patients.

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.

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.

[Osteoporosis in the patients with rheumatoid arthritis (3) : the efficacy and the selection of the osteoporosis therapeutic drug].

Osteoporosis and fragile fractures are common and preventable complication in rheumatoid arthritis (RA) . We recently reported that the frequency of osteoporosis among RA patients was 53.3%, that of vertebral fractures was 19.3%. They were much higher rates than those of general population. Earlier drug intervention is necessary to prevent these complications. RA patients with glucocorticoid (GC) should be treated according to "Guidelines on the management and treatment of glucocorticoid-induced osteoporosis" published by JBMSR in 2004. The bone of RA patients are likely to be in high-turnover state. Consequently bisphosphonates, especially alendronate and risedronate, are recommended to regulate bone metabolism, to increase bone mineral density and prevent incidental fractures in RA patients.

[Active vitamin D3 therapy for gulucocorticoid-induced osteoporosis].

Glucocorticoid-induced osteoporosis (GIO) is the most common secondary cause of osteoporosis. The use of glucocorticoid (GC) is associated with an increase in bone loss, especially at vertebral spine, and risk of fracture. Active vitamin D(3) (VD(3)) is expected to preserve bone mineral density at vertebral spine, however it is inferior to bisphosphonates (BP) with respect to preventing incidental vertebral fractures. In the guidelines on the management and treatment of GIO in Japan, VD(3) is recommended as the second-lined drug for GIO. The combination of VD(3) and BP is thought to be a beneficial therapy in prevention and or treatment of GIO.

Fatal complication of Legionella pneumophila pneumonia in a tocilizumab-treated rheumatoid arthritis patient.

We herein report a fatal case of Legionella pneumophila pneumonia in a tocilizumab-treated rheumatoid arthritis patient who was in a state of shock on admission but remained afebrile even during severe pneumonia. Legionella antigen was detected in the urine and neutrophil CD64 expression was highly elevated. Despite undergoing intensive treatment, the patient developed sepsis and died 12 days after admission. An autopsy indicated that while the Legionella infection had almost been controlled, a subarachnoid hemorrhage was the ultimate cause of death.

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.

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis.

OBJECTIVE: To compare the diagnostic utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies with other serological markers including rheumatoid factor (RF), anti-agalactosyl immunoglobulin G (IgG) antibody, and matrix metalloproteinase (MMP)-3 in very early rheumatoid arthritis (RA). METHODS: Serum concentrations of anti-CCP antibodies, RF, anti-agalactosyl IgG antibody, and MMP-3 were measured in 262 patients with RA ("total RA") including 55 patients with disease duration of less than 6 months who had not been treated before entry ("very early RA") and 116 patients with rheumatic diseases other than RA. RESULTS: The diagnostic sensitivity of anti-CCP antibodies was 82.4% in total RA and 67.3% in very early RA and was lower than that of RF (84.0% total RA, 83.6% very early RA) and anti-agalactosyl IgG antibody (90.5%, 90.9%), whereas specificity, positive predictive value, and diagnostic accuracy were the best among markers tested both in total RA and in very early RA. The presence of either anti-CCP antibodies or RF increased the sensitivity, but any combination of serological markers was not significantly better in diagnostic accuracy than anti-CCP antibodies alone. The rates of RF-positive subjects in anti-CCP antibody-negative patients both in total RA (43.5%) and in very early RA (61.1%) were higher than those of anti-CCP antibody-positive subjects in RF-negative patients (38.1% and 22.2%, for total RA and early RA, respectively). CONCLUSION: Measurement of anti-CCP antibodies, by itself, is useful for the diagnosis of RA; however, combined use of anti-CCP antibodies with RF may be more useful than either method alone for the diagnosis of very early RA.

CD64 on neutrophils is a sensitive and specific marker for detection of infection in patients with rheumatoid arthritis.

OBJECTIVE: In inflammatory diseases, differentiation between infection and disease flares is often clinically difficult because of similar signs and symptoms, such as fever and elevation of inflammatory markers. In rheumatoid arthritis (RA), infection is not only one of the major complications but also one of the frequent causes of death. Use of biologic agents such as tumor necrosis factor-a blockers has been reported to increase the incidence of tuberculosis or opportunistic infections. We examined the utility of CD64 (FcgRI) expressed on neutrophils as a marker for detection of infection complicated with RA. METHODS: We measured the expression level of CD64 per neutrophil quantitatively by flow cytometry in 279 samples from 237 patients with RA with various levels of disease activity or types of infection, and in 52 samples from 36 controls including subjects with infection. RESULTS: CD64 expression was significantly higher among RA patients with infection (median 4156 molecules per neutrophil, interquartile range 2583-8587) than in those without infection (884, IQR 670-1262) (p < or = 0.001). The sensitivity of CD64 on neutrophils for the diagnosis of infection (using a cutoff value of 2000 molecules per cell) was 92.7% and specificity was 96.5%. CD64 expression was not affected by the disease activity of RA or the use of corticosteroids, disease modifying antirheumatic drugs, and biologic agents. CD64 was upregulated in infection by bacteria, viruses, fungi, and mycobacteria. CONCLUSION: Our results suggest that quantitative measurement of CD64 expression on neutrophils can be used as a sensitive and specific marker to detect infection complicating RA.

Clinical characteristics of Pneumocystis carinii pneumonia in patients with connective tissue diseases.

The characteristics of Pneumocystis carinii pneumonia (PCP) in patients with connective tissue diseases (CTDs) were examined retrospectively. Nine patients were enrolled in this study. Their mean age was 57.1 years. All the patients received a high-dose steroid or immunosuppressant. The onset (mean 6.6 days) of fever, cough, breathlessness, and geographical ground-glass opacities revealed by chest computed tomography was acute. The serum beta-D: -glucan level increased with a simultaneous increase in the Krebs von den Lungen (KL)-6 or surfactant protein D level. The serum immunoglobulin G (IgG) and albumin levels and the peripheral blood lymphocyte count at the onset of PCP were low, but only the serum IgG level decreased significantly. The patients were treated with trimethoprim-sulfamethoxazole or pentamidine isetionate. Six patients died eventually: two patients of progressive respiratory failure, two probably due to a recurrence of the PCP, and two with microbial respiratory infections other than PCP. Five of the six patients required mechanical ventilation. Three patients received secondary prophylaxis and survived. In conclusion, the acute onset was characteristic of PCP in patients with CTDs. High-dose steroids, immunosuppressants, and hypogammaglobulinemia are risk factors; and respiratory failure requiring mechanical ventilation, severe secondary infections, and a lack of secondary prophylaxis are poor prognostic factors. Secondary prophylaxis is recommended for all of these patients.