Monocentric study of IL-5 monoclonal antibody induction therapy for eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: Although sporadic case reports have demonstrated successful management of eosinophilic granulomatosis with polyangiitis (EGPA) by anti-IL-5 therapy, larger-scale monocentric studies for the efficacy of mepolizumab (MEP), an IL-5 monoclonal antibody, are still lacking in Taiwan. METHODS: Hospitalized EGPA patients aged at least 18 years were enrolled from November 1998 to October 2023, and analyzed for demographic, clinical, laboratory, medication and outcome data, focusing on the efficacy and safety of biologics use, particularly induction therapy with MEP. RESULTS: Twenty-seven EGPA patients aged 10-70 years (43 ± 15) at disease diagnosis were recruited with 21 under combined corticosteroids/cyclophosphamide induction therapy. Seventeen patients received biologics with 13 under MEP therapy. Ten patients aged 19-71 years (48 ± 15) completed 12-month induction therapy with a 100 mg quadri-weekly subcutaneous injection regimen indicated for active or relapse disease. There were reduced BVAS with complete remission in 6 and partial remission in 4 patients, lower CRP levels, decreased eosinophil counts with an inhibition of 92∼96 %, and tapered prednisolone dosages from 5 to 25 (13.0 ± 6.3) to 0-10 (3.3 ± 3.1) mg/day. Only one patient had an adverse event of injection site reactions. Nine patients received the same regimen for annual maintenance therapy. All had a persistent clinical remission. In these patients, 13-56 injections (41 ± 15) were prescribed with a follow-up period of 12∼52 months (38 ± 14). CONCLUSION: In this retrospective study, induction therapy with a 12-month 100 mg MEP quadri-weekly subcutaneous injection regimen demonstrates the efficacy and safety for active and relapsing EGPA patients.

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.

High occurrence of autoimmune and lymphoproliferative manifestations in adults with common variable immunodeficiency in southernTaiwan.

There are no reported case series of common variable immunodeficiency (CVID) from southern Taiwan. A 20-year review was performed in adult CVID from a southern Taiwan medical center. Patients with ages of 18 years or older were enrolled from May, 2003 to April, 2023. Twelve patients were identified, 8 females/4 males aged 23 to 68 (38.9 ± 13.4) with one to 11 years (5.0 ± 3.3) delay of diagnosis after disease onset. There were concomitant autoimmune disorders in 7 (58 %), splenomegaly in 10 (83 %), lymphadenopathy in 4 (25 %) and B-cell lymphoma in 2 (17 %). All received intravenous immunoglobulin (IVIg) infusion with improved autoimmune-mediated arthritis in 2. Patients with higher IgG trough levels (above 500 mg/dL) had a better survival than those with lower IgG trough levels. Adult CVID in southern Taiwan has a high occurrence of autoimmune and lymphoproliferative manifestations. Early diagnosis with IVIg infusion might improve the presentations.

Long noncoding RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus.

BACKGROUND: Dysregulated long noncoding RNA (lncRNA) expression with increased apoptosis has been demonstrated in systemic lupus erythematosus (SLE) patients with alveolar hemorrhage (AH). SNHG16, a lncRNA, can enhance pulmonary inflammation by sponging microRNAs, and upregulate toll-like receptor 4 (TLR4) expression via stabilizing its mRNAs. TRAF6, a TLR4 downstream signal transducer, can induce autophagy and NETosis formation. In this study, we investigated whether SNHG16 could regulate TLR4-mediated autophagy and NETosis formation in SLE-associated AH. METHODS: Expression of SNHG16, TLR4 and TRAF6 and cell death processes were examined in lung tissues and peripheral blood (PB) leukocytes from AH patients associated with SLE and other autoimmune diseases, and in the lungs and spleen from a pristane-induced C57BL/6 mouse AH model. SNHG16-overexpressed or -silenced alveolar and myelocytic cells were stimulated with lipopolysaccharide (LPS), a TLR4 agonist, for analyzing autophagy and NETosis, respectively. Pristane-injected mice received the intra-pulmonary delivery of lentivirus (LV)-SNHG16 for overexpression and prophylactic/therapeutic infusion of short hairpin RNA (shRNA) targeting SNHG16 to evaluate the effects on AH. Renal SNHG16 expression was also examined in lupus nephritis (LN) patients and a pristane-induced BALB/c mouse LN model. RESULTS: Up-regulated SNHG16, TLR4 and TRAF6 expression with increased autophagy and NETosis was demonstrated in the SLE-AH lungs. In such patients, up-regulated SNHG16, TLR4 and TRAF6 expression was found in PB mononuclear cells with increased autophagy and in PB neutrophils with increased NETosis. There were up-regulated TLR4 expression and increased LPS-induced autophagy and NETosis in SNHG16-overexpressed cells, while down-regulated TLR4 expression and decreased LPS-induced autophagy and NETosis in SNHG16-silenced cells. Pristane-injected lung tissues had up-regulated SNHG16, TLR4/TRAF6 levels and increased in situ autophagy and NETosis formation. Intra-pulmonary LV-SNHG16 delivery enhanced AH through up-regulating TLR4/TRAF6 expression with increased cell death processes, while intra-pulmonary prophylactic and early therapeutic sh-SNHG16 delivery suppressed AH by down-regulating TLR4/TRAF6 expression with reduced such processes. In addition, there was decreased renal SNHG16 expression in LN patients and mice. CONCLUSIONS: Our results demonstrate that lncRNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in the human and mouse AH lungs, and provide a therapeutic potential of intra-pulmonary delivery of shRNA targeting SNHG16 in this SLE-related lethal manifestation.

Galectin-3 Mediates NETosis and Acts as an Autoantigen in Systemic Lupus Erythematosus-Associated Diffuse Alveolar Haemorrhage.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with enhanced NETosis and impaired degradation of neutrophil extracellular traps (NETs). Galectin-3 is a ß-galactoside binding protein and is associated with neutrophil functions as well as involved in mediating autoimmune disorders. In this study, we plan to examine the associations of galectin-3 with the pathogenesis of SLE and NETosis. Galectin-3 expression levels were determined in peripheral blood mononuclear cells (PBMCs) of SLE patients for the association with lupus nephritis (LN) or correlation of SLE disease activity index 2000 (SLEDAI-2K). NETosis was observed in human normal and SLE and murine galectin-3 knockout (Gal-3 KO) neutrophils. Gal-3 KO and wild-type (WT) mice induced by pristane were used to evaluate disease signs, including diffuse alveolar haemorrhage (DAH), LN, proteinuria, anti-ribonucleoprotein (RNP) antibody, citrullinated histone 3 (CitH3) levels, and NETosis. Galectin-3 levels are higher in PBMCs of SLE patients compared with normal donors and positively correlated with LN or SLEDAI-2K. Gal-3 KO mice have higher percent survival and lower DAH, LN proteinuria, and anti-RNP antibody levels than WT mice induced by pristane. NETosis and citH3 levels are reduced in Gal-3 KO neutrophils. Furthermore, galectin-3 resides in NETs while human neutrophils undergo NETosis. Galectin-3-associated immune complex deposition can be observed in NETs from spontaneously NETotic cells of SLE patients. In this study, we provide clinical relevance of galectin-3 to the lupus phenotypes and the underlying mechanisms of galectin-3-mediated NETosis for developing novel therapeutic strategies targeting galectin-3 for SLE.

Seronegative spondyloarthropathy-associated inflammatory bowel disease.

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

Autoimmune liver diseases in systemic rheumatic diseases.

Systemic rheumatic diseases (SRDs) are chronic, inflammatory, autoimmune disorders with the presence of autoantibodies that may affect any organ or system. Liver dysfunction in SRDs can be associated with prescribed drugs, viral hepatitis, alternative hepatic comorbidities and coexisting autoimmune liver diseases (AILDs), requiring an exclusion of secondary conditions before considering liver involvement. The patterns of overlap diseases depend predominantly on genetic determinants with common susceptible loci widely distributing in both disorders. In AILDs, it is important to identify the overlapping SRDs at an early stage since such a coexistence may influence the disease course and prognosis. Commonly co-occurring SRDs in AILDs are Sjögren syndrome (SS), rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) in autoimmune hepatitis (AIH), and SS, RA or systemic sclerosis in primary biliary cholangitis. Owing to different disease complications and therapies, it is imperative to differentiate between SLE liver involvement and SLE-AIH overlap disease. Therapeutic options can be personalized to control coexisting conditions of liver autoimmunity and rheumatic manifestations in AILD-SRD overlap diseases. The collaboration between hepatologists and rheumatologists can lead to significant advances in managing such a complex scenario. In this review, we provide a comprehensive overview on coexisting AILDs in different SRDs and the therapeutic approach in managing these overlap diseases.

Down-regulated miR-146a expression with increased neutrophil extracellular traps and apoptosis formation in autoimmune-mediated diffuse alveolar hemorrhage.

BACKGROUND: Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer. METHODS: Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH. RESULTS: In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression. CONCLUSIONS: Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery.

Acute rheumatic fever in adult patients.

Acute rheumatic fever (ARF) is considered as a disorder of children, and attacks in adults are usually a recurrence of disease acquired in the child's life. Although the incidence of ARF in children has a decreasing trend in developed countries, resurgent and sporadic epidemics still occur in adults. The first attacks of ARF in adult patients without a childhood history can lead to a diagnostic dilemma. A medical record review in adults at least 18 years of age with an arthralgia complaint fulfilling 2015 revised Jones criteria was performed from January 1, 2000 to December 31, 2019. Eleven ARF patients were identified, including 8 with initial attacks (6 females aged 26-42 years, 33.9 ± 5.3) and 3 pre-existing valvular heart disease with recurrent attacks (2 females aged 38-52 years, 45.0 ± 7.0). In addition to febrile pharyngitis and migratory polyarthritis in initial attacks, pericarditis was encountered in 1, valvulitis in 2, prolong PR interval in 3 and skin involvement in 2 patients with erythema marginatum and IgA vasculitis. All responded to antibiotics and nonsteroidal anti-inflammatory drugs therapy with normalized clinical and laboratory abnormalities, no new-onset carditis, and no recurrent disease during a long-term follow-up (3.8-19.8 years, 12.7 ± 5.4). A sporadic occurrence of adult ARF is observed in southern Taiwan. This disease should be considered by physicians for the differential diagnosis of febrile pharyngitis with arthritis and/or carditis in adults, even in areas with a low incidence of ARF.

Immediate-release tofacitinib reduces insulin resistance in non-diabetic active rheumatoid arthritis patients: A single-center retrospective study.

BACKGROUND: An increased risk of insulin resistance (IR) has been identified in rheumatoid arthritis (RA), a chronic inflammatory disorder with elevated levels of pathogenic cytokines. Biologics targeting proinflammatory cytokines can control the disease and improve insulin sensitivity in RA. Although Janus kinase (JAK) signaling can regulate cytokine receptors and participate in RA pathogenesis, it remains to be elucidated whether there is a reduction of IR in such patients under JAK inhibitor (JAKi) therapy. AIM: To study the effect of JAKi treatment on the reduction of IR in RA patients with active disease. METHODS: A retrospective study was carried out from April 1, 2017 to March 31, 2021 in a population of non-diabetic patients with active RA who were undergoing tofacitinib (TOF) therapy with 5 mg twice-daily immediate-release formulation. RESULTS: Fifty-six RA patients, aged 30 years to 75 years (mean ± SD: 52.3 ± 11.1) with disease activity score 28 values ranging from 4.54 to 7.37 (5.82 ± 0.74), were classified into high-IR (> 2.0) and low-IR (≤ 2.0) groups based on their baseline homeostatic model assessment (HOMA)-IR levels. They had no previous exposure to JAKi, and received TOF therapy for no less than 6 mo. In 30 patients who were naïve to biologics, after a 24-week therapeutic period, the high-IR group showed reduced HOMA-IR levels (3.331 ± 1.036 vs 2.292 ± 0.707, P < 0.001). In another 26 patients who were exposed to tumor necrosis factor-α or interleukin-6 blockers, the high-IR group, despite having achieved a decrease but with lower magnitude than in naïve patients, showed reduced HOMA-IR levels (2.924 ± 0.790 vs 2.545 ± 1.080, P = 0.018). CONCLUSION: In this retrospective study, reduced IR was achieved in non-diabetic active RA patients following 24 wk of TOF therapy.

Extended-release tofacitinib for refractory Behçet disease: A case report.

RATIONALE: Although single-cytokine inhibitors can be considered in treating severe or refractory Behçet disease (BD), these biologic agents are associated with potential therapeutic failure due to the multi-cytokine pathogenesis involving Th1- and Th17-type cytokines with activated Janus kinase/signal transducer and activator of transcription signaling pathways. Notably, there is an increasing trend toward the use of small-molecule targeted drug tofacitinib (TOF), a pan-Janus kinase inhibitor, with immediate-release formulations for treating patients with severe or refractory systemic vasculitis involving different vessel sizes. Despite no reported efficacy of extended-release formulations in refractory BD yet, such a dosage form has pharmacokinetic parameters that are comparable to those of conventional immediate-release formulations. PATIENT CONCERNS AND DIAGNOSIS: We report the case of a 27-year-old local woman with recurrent manifestations of arthritis, orogential ulcerations, papulopustular lesions, and anterior uveitis. She was diagnosed with BD for more than 3 years, and received long-term corticosteroids plus immunosuppressants therapy with the complication of opportunistic candidiasis infection. INTERVENTIONS AND OUTCOMES: Under extended-release TOF 11 mg once-daily therapy, the patient achieved disease remission while sparing the use of corticosteroids during follow-up. LESSONS: Our clinical observations implicate the oral convenience and therapeutic efficacy of extended-release TOF formulations in controlling the disease activity of BD.

Pelvic deep venous thrombosis mimicking lower limb cellulitis in systemic lupus erythematosus-associated antiphospholipid syndrome.

OBJECTIVES: Systemic lupus erythematosus (SLE) associated with antiphospholipid syndrome (APS) is a complex clinical scenario with thromboembolic events, lupus activity, and related therapeutic complications like infection. In SLE, iliofemoral (IF) deep vein thrombosis (DVT) with fever and erythematous swollen limbs mimic cellulitis over lower extremities. Nevertheless, to distinguish DVT from cellulitis is imperative in clinical practice due to the use of different therapeutic regimens. METHODS: A retrospective study was performed to analyze iliofemoral DVT in hospitalized SLE-associated APS patients with fever and erythematous swollen limbs mimicking cellulitis from January 1, 2011 to December 31, 2020. RESULTS: Among 896 hospitalized SLE patients, 117 were associated with APS. Three patients had pelvic IF DVT with total vascular occlusion, presenting as fever and erythematous swollen limbs mimicking cellulitis. Despite negative duplex sonographic findings, IF thrombi were demonstrated by using computed tomography and/or catheter venography. Owing to refractory to unfractionated or low-molecular-weight heparin injection, all received the thrombolytic treatment. Complete resolution of thrombi without recurrent DVT and post-thrombotic syndrome was identified in two patients receiving pharmacomechanical thrombectomy or catheter-directed thrombolysis. CONCLUSIONS: For differential diagnosis of IF DVT and lower limb cellulitis in SLE-associated APS, our case series underlines the importance of venography to detect an unusual pelvic location of thrombi.

B-Cell-Depleting Therapy Improves Myocarditis in Seronegative Eosinophilic Granulomatosis with Polyangiitis.

Cardiac involvement is a major mortality cause in eosinophilic granulomatosis with polyangiitis (EGPA), requiring novel therapeutics to spare the use of cyclophosphamide with known cardiotoxicity. Despite the observed efficacy of B-cell-depleting therapy in myocarditis of seropositive microscopic polyangiitis, it remains to be elucidated in seronegative EGPA. A retrospective study was performed in 21 hospitalized active patients aged 20 to 70 years with five-factor score 1 or 2, eosinophil counts 10,034 ± 6641/µL and vasculitis scores 27 ± 6. Overt myocarditis was identified in 10 cases, at disease onset in 6 and relapse in 4, with endomyocarditis in 4 and myopericarditis in 4. Five seronegative and one seropositive patient received rituximab with an induction regimen 375 mg/m2 weekly × 4 for refractory or relapse disease, and the same regimen for annual maintenance therapy. All cases had lower eosinophil counts, improved cardiac dysfunction and clinical remission with a relapse-free follow-up, 48 ± 15 months after the induction treatment. One seronegative endomyocarditis patient had eosinophilia and disease relapse with asthma attack and worsening cardiac insufficiency 24 months after induction, achieving clinical remission under anti-IL-5 therapy. Our findings suggest the suppression of IL-5-mediated eosinophilia as an action mechanism of B-cell-depleting therapy in seronegative EGPA myocarditis.