Extended-Release Tofacitinib Therapy for a MDA5 Antibody-Positive Amyopathic Dermatomyositis Patient with Early-Stage Interstitial Lung Disease.

Introduction: In East Asia, more than half of patients with amyopathic dermatomyositis (ADM) have interstitial lung disease (ILD). There is up to 50% 6-month mortality in MDA5-positive ILD refractory to corticosteroid (CS) combined with immunosuppressant therapy. Patient Details: A 39-year-old local woman had a 1-month history of reddish-purple discoloration around the eyelids (heliotrope rash), and erythematous areas on the upper back and posterior neck (shawl sign) as well as on the front of her chest (V sign), followed by dry cough and mild dyspnea for 1 week. She had normal muscle strength, muscle-enzyme concentrations, and muscular magnetic resonance images. Laboratory tests showed hypoxemia, increased ferritin and CRP levels, and positive MDA5 antibodies. High-resolution chest computed tomography revealed bilateral ground-glass opacity. She received a diagnosis of anti-MDA5-positive ADM with early-stage ILD. Intervention: Pulse methylprednisolone and cyclophosphamide therapies were initiated, followed by high-dose CS treatment. Immediate-release twice-daily 5 mg tofacitinib (Tof) has been demonstrated to be effective induction therapy for early-stage ILD in anti-MDA5-positive ADM. Owing to the patient's preference for once-daily therapy, 11 mg extended-release Tof was prescribed 4 weeks after starting the initial pulse CS treatment for ILD. Outcomes: Respiratory symptoms and cutaneous manifestations were absent and the use of CS spared 5 months after initiating Tof therapy. Laboratory examinations exhibited normalized ferritin/oxygen levels, and chest images displayed completely resolved pulmonary infiltration. ILD remains under adequate control with Tof monotherapy without recurrence at 5 months. Lessons: Owing to a rapid decline in higher mortality in anti-MDA5-positive ADM patients with ILD, early detection with prompt initiation of extended-release Tof induction therapy might achieve a beneficial outcome.

Brief report: amelioration of collagen-induced arthritis in mice by lentivirus-mediated silencing of microRNA-223.

OBJECTIVE: MicroRNA (miRNA) plays a role in autoimmune diseases. MiRNA-223 (miR-223) is up-regulated in patients with rheumatoid arthritis (RA) and is involved in osteoclastogenesis, which contributes to erosive disease. The aim of this study was to test the feasibility of using lentiviral vectors expressing the miR-223 target sequence (miR-223T) to suppress miR-223 activity as a therapeutic strategy in a mouse model of collagen-induced arthritis (CIA). METHODS: Levels of miR-223 in the synovial tissue of patients with RA or osteoarthritis (OA), as well as in the ankle joints of mice with CIA, were determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Lentiviral vectors expressing miR-223T (LVmiR-223T) or luciferase short hairpin RNA (LVshLuc) as a control vector were injected intraperitoneally into mice with CIA. Treatment responses and disease-related bone mineral density were monitored. Levels of nuclear factor 1A (NF-1A), a direct target of miR-223, and macrophage colony-stimulating factor receptor (M-CSFR), which is critical for osteoclastogenesis, were measured by immunohistochemistry and quantitative RT-PCR. Osteoclasts were assessed by tartrate-resistant acid phosphatase staining. RESULTS: MiR-223 expression was significantly higher in the synovium of RA patients and in the ankle joints of mice with CIA as compared to OA patients and normal mice. LVmiR-223T treatment reduced the arthritis score, histologic score, miR-223 expression, osteoclastogenesis, and bone erosion in mice with CIA. Down-regulation of miR-223 with concomitant increases in NF-1A levels and decreases in M-CSFR levels was detected in the synovium of LVmiR-223T-treated mice. CONCLUSION: This study is the first to demonstrate that lentivirus-mediated silencing of miR-223 can reduce disease severity of experimental arthritis. Furthermore, our results indicate that inhibition of miR-223 activity should be further explored as a therapeutic strategy in RA.

Amelioration of rat collagen-induced arthritis through CD4+ T cells apoptosis and synovial interleukin-17 reduction by indoleamine 2,3-dioxygenase gene therapy.

Indoleamine 2,3-dioxygenase (IDO) has been known as an emerging therapeutic target in autoimmunity-related arthritis. The treatment responses of adenoviral vectors encoding IDO (AdIDO) gene therapy in rat collagen-induced arthritis (CIA) were examined in this study. The therapeutic effects on ankle circumference, articular index, and radiographic and histological scores were evaluated in AdIDO-injected ankle joints. We further determined CD4+ T-cell numbers and their apoptotic status, CD68(+) macrophage numbers, kynurenine (a downstream tryptophan metabolite) concentrations, interleukin-17 (IL-17) levels, and retinoic acid-related orphan receptor γt (RORγt) expression in synovial tissues of CIA rats receiving AdIDO treatment. Reduction of ankle circumference, articular index, and radiographic and histological scores were noted in AdIDO-treated ankles, as compared with those receiving injection of control vectors. Furthermore, IDO gene transfer led to decreased infiltrating CD4+ T cells with enhanced apoptosis, reduced CD68+ macrophage numbers, increased kynurenine levels, lower IL-17 concentrations, and decreased RORγt expression within the ankle joints. In addition, such a therapy diminished type II collagen-specific IL-17 production and RORγt expression in CD4+ T cells from draining lymph nodes of CIA rats. Our results demonstrate for the first time that intra-articular delivery of IDO gene ameliorated ankle arthritis of CIA rats by induction of CD4+ T-cell apoptosis and reduction of synovial IL-17 production through the supplement of kynurenine. Taken together, these findings implicate the novel strategy of using IDO gene as a therapeutic approach in treating patients with rheumatoid arthritis.

Adult-onset acute rheumatic fever: possible resurgence in southern Taiwan.

BACKGROUND: By the late 1980s, acute rheumatic fever (ARF) had become a rare disease in Taiwan. The low prevalence rate in this area is attributed to a better economic status, which has led to improved public health and adequate medical services. OBJECTIVES: The increasing number of patients with adult-onset ARF in the United States described in the literature prompted us to evaluate the cases diagnosed in our medical center. METHODS: A retrospective chart review was performed for patients with arthritis from July 1988 to October 2004. To be included, patients had to meet revised Jones criteria. RESULTS: Three adult patients with ARF have been diagnosed since June 2001, with no childhood ARF being diagnosed. All cases presented with migratory polyarthritis, whereas 1 had erythema marginatum and transient carditis. These patients responded well to treatment with antibiotics and nonsteroidal antiinflammatory drugs. CONCLUSIONS: Clinicians must provide careful assessment and treatment to patients presenting with acute pharyngitis. A possible resurgence of ARF can be eradicated by primary prevention of streptococcal pharyngitis.