Recommendations for physical activity and exercise in persons living with Systemic Lupus Erythematosus (SLE): consensus by an international task force.

OBJECTIVE: This international task force aimed to provide healthcare professionals and persons living with systemic lupus erythematosus (SLE) with consensus-based recommendations for physical activity and exercise in SLE. METHODS: Based on evidence from a systematic literature review and expert opinion, 3 overarching principles and 15 recommendations were agreed on by Delphi consensus. RESULTS: The overarching principles highlight the importance of shared decision-making and the need to explain the benefits of physical activity to persons living with SLE and other healthcare providers. The 15 specific recommendations state that physical activity is generally recommended for all people with SLE, but in some instances, a medical evaluation may be needed to rule out contraindications. Pertaining to outdoor activity, photoprotection is necessary. Both aerobic and resistance training programmes are recommended, with a gradual increase in frequency and intensity, which should be adapted for each individual, and ideally supervised by qualified professionals. CONCLUSION: In summary, the consensus reached by the international task force provides a valuable framework for the integration of physical activity and exercise into the management of SLE, offering a tailored evidence-based and eminence-based approach to enhance the well-being of individuals living with this challenging autoimmune condition.

Correlation of Hematological Indices and Acute-Phase Reactants in Rheumatoid Arthritis Patients on Disease-Modifying Antirheumatic Drugs: A Retrospective Cohort Analysis.

Acute-phase markers are often used to evaluate the disease activity of rheumatoid arthritis (RA). Occasionally, the serum levels of acute-phase reactants remain normal in patients with obvious inflamed joints. Hematological indices derived from complete blood counts have been shown to correlate with disease activity. This provides a potential practical implementation in daily practice. Only a few studies have evaluated the relation between hematological indices and novel RA treatment (i.e., biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs); no research has examined the changes in hematological indices in RA treatments longitudinally. We conducted a retrospective study involving 273 RA patients with b/tsDMARD treatment and followed them for at least a year. Baseline, 3-month, and 6-month lab data were collected. The results indicated a reduction in the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) post-treatment. Higher baseline PLRs and SIIs were associated with a more significant reduction in ESR at three months (η2 = 0.03/0.13, p = 0.21/0.023). NLR and SII correlated with CRP moderately at three months (r = 0.373/0.394, p < 0.001/< 0.001). A correlation comparison showed that the correlation of NLR and PLR with CRP differs during different periods (p = 0.037/0.004). Subgroup analysis revealed that the time effect on correlation is related to treatment with Janus kinase inhibitor and anti-interleukin-6 but not antitumor necrosis factors.

Acute Orbital Apex Syndrome Caused by Idiopathic Sclerosing Orbital Inflammation.

Idiopathic sclerosing orbital inflammation (ISOI) is a distinct entity among other orbital diseases. It is characterized by marked fibrosis and inflammatory cell infiltration that can damage orbital structures. Clinical manifestations were variable, including ocular and periocular redness, proptosis, and pain. Ocular motor restrictions and optic nerve dysfunction might occur in severe cases. We herein report a patient of ISOI who presented with total ophthalmoplegia and acute vision loss. His symptoms were relieved mainly as his vision improved to 20/25 after receiving corticosteroid and immunosuppressant therapies. Therefore, ISOI should be one of the deferential diagnoses when we encounter cases with acute orbital apex syndrome. With prompt evaluation and in-time treatment, a favorable outcome is possible.

Idiopathic Multicentric Castleman Disease with Strikingly Elevated IgG4 Concentration in the Serum and Abundant IgG4-Positive Cells in the Tissue: A Case Report.

Idiopathic multicentric Castleman disease (iMCD) can be challenging to distinguish clinically and histopathologically from Immunoglobulin G4-related disease (IgG4RD). A 73-year-old man was referred to a rheumatologist for suspected autoimmune-related polyclonal hypergammaglobulinemia. The patient had a history of multiple lymphadenopathies in the neck for over 20 years. Laboratory data showed elevated serum immunoglobulin G4 (IgG4) levels, hypergammaglobulinemia, high C-reactive protein (CRP) levels, marked anemia, and positivity for several autoantibodies. Additionally, imaging studies revealed multiple enlarged lymph nodes and multifocal, ill-defined, small patchy opacities over the lung. Biopsies of the neck lymph node and right lung revealed typical features of multicentric Castleman disease (MCD). Immunohistochemical staining was negative for human herpesvirus-8 (HHV-8) in both lymph nodes and the right lung, sub-classified as iMCD, whereas the IgG4/IgG ratio was >40%, which raised the suspicion of IgG4RD. However, serological cytokine analysis demonstrated an increased interleukin-6 (IL-6) level, alongside systemic inflammatory and histopathological features, distinguishing MCD from IgG4RD in this patient. The patient was treated with short-term glucocorticoids and regular infusion of an anti-IL-6 receptor monoclonal antibody (tocilizumab), with satisfactory clinical and radiographic responses. Notably, differentiating MCD from IgG4RD is crucial for optimal treatment. Clinical and pathological features may assist in distinguishing between these two diseases.

Effects of Biological/Targeted Therapies on Bone Mineral Density in Inflammatory Arthritis.

Inflammatory arthritis has been reported to be associated with the development of osteoporosis. Recent research has investigated the mechanisms of bone metabolism in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Progress in both animal and clinical studies has provided a better understanding of the osteoclastogenesis-related pathways regarding the receptor activator of nuclear factor-κB ligand (RANKL), anti-citrullinated protein antibodies (ACPAs), and Wnt signaling and Dickkopf-related protein 1 (Dkk-1). The complex interplay between inflammatory cytokines and bone destruction has been elucidated, especially that in the interleukin-17/23 (IL-17/23) axis and Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling. Moreover, advances in biological and targeted therapies have achieved essential modifications to the bone metabolism of these inflammatory arthritis types. In this narrative review, we discuss recent findings on the pathogenic effects on bone in RA and SpA. Proinflammatory cytokines, autoantibodies, and multiple signaling pathways play an essential role in bone destruction in RA and SpA patients. We also reviewed the underlying pathomechanisms of bone structure in biological and targeted therapies of RA and SpA. The clinical implications of tumor necrosis factor inhibitors, abatacept, rituximab, tocilizumab, Janus kinase inhibitors, and inhibitors of the IL-17/23 axis are discussed. Since these novel therapeutics provide new options for disease improvement and symptom control in patients with RA and SpA, further rigorous evidence is warranted to provide a clinical reference for physicians and patients.

Autologous stem cell transplantation in a patient with systemic sclerosis-associated interstitial lung disease in Taiwan.

BACKGROUND: Systemic sclerosis (SSc), characterized by fibrosis of the skin and other organs, is a devastating systemic autoimmune disease. Lung involvement is frequent in SSc and contributes to the high rate of mortality. OBJECTIVE: To describe the first case report of SSc and interstitial lung disease (ILD) receiving autologous hematopoietic stem cell transplantation (ASCT) in Taiwan. METHODS: Case report. RESULTS: A 51-year-old man presented with rapid skin thickening and shortness of breath. Early progressive SSc-associated ILD was diagnosed. Because his lung function rapidly declined and his skin disease progressed, he received ASCT with satisfactory treatment responses in both skin thickness and lung function. In addition, lung imaging analysis showed remarkable improvements in ILD after treatment. CONCLUSIONS: We suggest that ASCT can be considered in selected patients with early, rapidly progressive SSc associated with ILD.

Acute motor and sensory axonal neuropathy in association with primary Sjögren's syndrome: a case report.

BACKGROUND: Primary Sjögren's syndrome is a chronic, autoimmune, connective tissue disorder that results from the infiltration of exocrine glands, especially the lacrimal and salivary glands, by autoantibodies. Patients with Sjögren's syndrome commonly present with dry eyes (xerophthalmia) and dry mouth (xerostomia). However, the clinical manifestations of Sjögren's syndrome can be complicated and variable due to involvement of extraglandular organ systems, such as the nervous system. The neurological manifestations of this disorder often precede those of other exocrine gland symptoms. Hence, early diagnosis of Sjögren's syndrome remains a challenge. CASE PRESENTATION: We report the case of a 63-year-old woman with primary Sjögren's syndrome who presented with acute motor and sensory axonal neuropathy (AMSAN). Treatment with glucocorticoids and immunosuppressants partially improved her muscle weakness and paresthesia. CONCLUSIONS: This case demonstrates the importance of early recognition and diagnosis of AMSAN in association with primary Sjögren's syndrome to achieve a favorable clinical outcome. Primary Sjögren's syndrome may be underdiagnosed because of vague symptoms of the sicca complex. Comprehensive immunological testing to evaluate this condition may be performed in patients presenting with variants of Guillain-Barré syndrome.

Combined aerobic and resistance training improves physical and executive functions in women with systemic lupus erythematosus.

OBJECTIVES: Exercise is considered as an adjuvant therapeutic modality to alleviate symptoms of several rheumatic diseases. However, data regarding the benefits of exercise to patients with systemic lupus erythematosus (SLE) are relatively scant. METHODS: This study aimed to assess the effects of regular, moderate-intensity, aerobic exercise combined with resistance training on women with SLE who had no regular exercise. Patients were recruited and allocated into either the exercise or control group by their willingness. Patients in the exercise group (n = 12) underwent 12 weeks of combined exercise (five days per week), whereas those in the control group (n = 11) maintained their usual lifestyle. RESULTS: At baseline, there were no between-group differences in body composition, disease activity, two-kilometer walking test, and executive function test. After the combined exercise intervention for 12 weeks, significant improvements of both fitness index and reaction time to the stimuli in the go/no-go test were observed in the exercise group, but not in the control group. The disease activities in both study groups did not change significantly at the end of the study period. CONCLUSION: Our results suggest that regular moderate-intensity aerobic exercise combined with resistance training improves the physical and executive functions of SLE patients without exacerbating disease activity.

Updates on the diagnosis and management of multicentric Castleman disease.

Multicentric Castleman disease (MCD) is an uncommon systemic lymphoproliferative disease. The diagnosis of this disease is typically challenging and requires collaboration between clinicians and pathologists. Moreover, it is important to exclude other diseases (such as malignancies, autoimmune diseases, and infectious diseases) that have similar clinical manifestations and pathological findings. Patients with untreated severe MCD have high mortality due to devastating cytokine storms. Thus, early diagnosis and prompt treatment is a key imperative. The diagnosis of MCD is based on the clinical signs of systemic inflammation, serological tests, and typical pathological features. In this review article, we provide an overview of MCD with a focus on the emerging evidence pertaining to its diagnosis and treatment.

Bone Mineral Density, Osteoporosis, and Fracture Risk in Adult Patients with Psoriasis or Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: Awareness of psoriasis-related comorbidities has been established in the current guidelines; however, evidence regarding the association of bone density or bone fragility with psoriatic disease remains inconclusive. METHODS: We conducted a systematic review and meta-analysis to assess bone mineral density and the risk of osteoporosis and fractures in patients with psoriatic disease, including those with cutaneous psoriasis and psoriatic arthritis. We searched electronic databases for published observational studies. A meta-analysis was performed using the random-effect model. Pooled estimates and their confidence intervals (CIs) were calculated. Small-study effects were examined using the Doi plot and Luis Furuya-Kanamori index. RESULTS: The analysis of the standardized mean difference in the absolute value of bone mineral density at different measuring sites (lumbar spine, femoral neck, and total hip) revealed no significant difference between patients with psoriatic disease and non-psoriatic controls. The pooled results of the adjusted odds ratios (ORs) demonstrated no increased risk of osteoporosis in patients with psoriatic disease. Notably, patients with psoriatic disease had a higher OR of developing bone fractures (adjusted OR: 1.09; 95% CI: 1.06 to 1.12; I2: 0%). CONCLUSION: Patients with psoriatic disease may be more likely to develop fractures compared with non-psoriatic controls. This higher risk for fracture may not necessarily be associated with lower bone mineral density nor a higher risk for osteoporosis.

Self-tolerance curtails the B cell repertoire to microbial epitopes.

Immunological tolerance removes or inactivates self-reactive B cells, including those that also recognize cross-reactive foreign antigens. Whereas a few microbial pathogens exploit these "holes" in the B cell repertoire by mimicking host antigens to evade immune surveillance, the extent to which tolerance reduces the B cell repertoire to foreign antigens is unknown. Here, we use single-cell cultures to determine the repertoires of human B cell antigen receptors (BCRs) before (transitional B cells) and after (mature B cells) the second B cell tolerance checkpoint in both healthy donors and in patients with systemic lupus erythematosus (SLE) . In healthy donors, the majority (~70%) of transitional B cells that recognize foreign antigens also bind human self-antigens (foreign+self), and peripheral tolerance halves the frequency of foreign+self-reactive mature B cells. In contrast, in SLE patients who are defective in the second tolerance checkpoint, frequencies of foreign+self-reactive B cells remain unchanged during maturation of transitional to mature B cells. Patterns of foreign+self-reactivity among mature B cells from healthy donors differ from those of SLE patients. We propose that immune tolerance significantly reduces the scope of the BCR repertoire to microbial pathogens and that cross-reactivity between foreign and self epitopes may be more common than previously appreciated.

Efficient Culture of Human Naive and Memory B Cells for Use as APCs.

The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B cell culture is the capacity to support mature B cell proliferation. We developed a culture method to support the efficient activation and proliferation of naive and memory human B cells. This culture supports extensive B cell proliferation, with ∼103-fold increases following 8 d in culture and 106-fold increases when cultures are split and cultured for 8 more days. In culture, a significant fraction of naive B cells undergo isotype switching and differentiate into plasmacytes. Culture-derived (CD) B cells are readily cryopreserved and, when recovered, retain their ability to proliferate and differentiate. Significantly, proliferating CD B cells express high levels of MHC class II, CD80, and CD86. CD B cells act as APCs and present alloantigens and microbial Ags to T cells. We are able to activate and expand Ag-specific memory B cells; these cultured cells are highly effective in presenting Ag to T cells. We characterized the TCR repertoire of rare Ag-specific CD4+ T cells that proliferated in response to tetanus toxoid (TT) presented by autologous CD B cells. TCR Vß usage by TT-activated CD4+ T cells differs from resting and unspecifically activated CD4+ T cells. Moreover, we found that TT-specific TCR Vß usage by CD4+ T cells was substantially different between donors. This culture method provides a platform for studying the BCR and TCR repertoires within a single individual.

The human fetal lymphocyte lineage: identification by CD27 and LIN28B expression in B cell progenitors.

CD27, a member of the TNFR superfamily, is used to identify human memory B cells. Nonetheless, CD27(+) B cells are present in patients with HIGM1 syndrome who are unable to generate GCs or memory B cells. CD27(+)IgD(+) fetal B cells are present in umbilical cord blood, and CD27 may also be a marker of the human B1-like B cells. To define the origin of naïve CD27(+)IgD(+) human B cells, we studied B cell development in both fetal and adult tissues. In human FL, most CD19(+) cells coexpressed CD10, a marker of human developing B cells. Some CD19(+)CD10(+) B cells expressed CD27, and these fetal CD27(+) cells were present in the pro-B, pre-B, and immature/transitional B cell compartments. Lower frequencies of phenotypically identical cells were also identified in adult BM. CD27(+) pro-B, pre-B, and immature/transitional B cells expressed recombination activating gene-1, terminal deoxynucleotidyl transferase and Vpre-B mRNA comparably to their CD27(-) counterparts. CD27(+) and CD27(-) developing B cells showed similar Ig heavy chain gene usage with low levels of mutations, suggesting that CD27(+) developing B cells are distinct from mutated memory B cells. Despite these similarities, CD27(+) developing B cells differed from CD27(-) developing B cells by their increased expression of LIN28B, a transcription factor associated with the fetal lymphoid lineages of mice. Furthermore, CD27(+) pro-B cells efficiently generated IgM(+)IgD(+) immature/transitional B cells in vitro. Our observations suggest that CD27 expression during B cell development identifies a physiologic state or lineage for human B cell development distinct from the memory B cell compartment.

Chronic aspiration shifts the immune response from adaptive immunity to innate immunity in a murine model of asthma.

OBJECTIVE AND DESIGN: The hypothesis that aspiration of gastric fluid drives the anti-ovalbumin response toward a Th2 reaction even in animals not prone to Th2 responses was evaluated. SUBJECTS: Forty-eight male C57BL/6 mice were used. METHODS: Mice were sensitized and challenged with ovalbumin starting 5 weeks prior to the initiation of weekly aspirations of either gastric fluid or normal saline as a control. Weekly aspiration continued during the course of exposure to ovalbumin. TREATMENT: Aspiration consisted of 50 µl of gastric fluid with 50 µl of 0.9 % normal saline used as a control. Antigen exposure consisted of sensitization to ovalbumin via intraperitoneal injection on days 0 and 14 and challenge on day 21 with aerosolized antigen for 30 min. RESULTS: No evidence of a shift toward a Th2 response as a result of gastric fluid aspiration was seen in the Th1-prone strain utilized, although a profound down-regulation of a broad array of T cell-associated cytokines and chemokines and up-regulation of macrophage-associated markers was observed as a result of aspiration. CONCLUSIONS: These data provide support for the hypothesis that the clinical association between asthma and gastroesophageal reflux disease (GERD) does not involve an exacerbation of asthma by GERD-associated aspiration of gastric fluid, but may cause immune reactions unrelated to the asthma pathology.

Lymphocyte phenotypes in wild-caught rats suggest potential mechanisms underlying increased immune sensitivity in post-industrial environments.

The immune systems of wild rats and of laboratory rats can been utilized as models of the human immune system in pre-industrial and post-industrial societies, respectively. In this study, lymphocyte phenotypes in wild rats were broadly characterized, and the results were compared to those obtained by us and by others using cells derived from various strains of laboratory rats. Although not expected, the production of regulatory T cells was not apparently different in wild rats compared to laboratory rats. On the other hand, differences in expression of markers involved in complement regulation, adhesion, signaling and maturation suggest increased complement regulation and decreased sensitivity in wild-caught rats compared to laboratory rats, and point toward complex differences between the maturation of T cells. The results potentially lend insight into the pathogenesis of post-industrial epidemics of allergy and autoimmune disease.

Incorporation of secretory immunoglobulin A into biofilms can decrease their resistance to ciprofloxacin.

Extracellular matrices utilized by biofilms growing on inert surfaces are generally produced entirely by the bacteria growing within those biofilms, whereas symbiotic (mutualistic) biofilms growing in or on a wide range of plants and animals utilize host-derived macromolecules, such as mucoid substances, as components of their extracellular matrix. Incorporation of host-derived molecules may have a profound effect on the resistance to antibiotics of symbiotic biofilms, which may have important implications for medicine and biology. As an initial probe of the potential effects of host-derived molecules in the extracellular matrix on the sensitivity of biofilms to antibiotics, an in vitro model was used to evaluate the effects of ciprofloxacin on biofilms grown in the presence and absence of SIgA, a host-derived glycoprotein associated with biofilms in the mammalian gut. In five out of six strains of Escherichia coli tested, the incorporation of SIgA into the biofilms apparently reduced the resistance of the bacteria to ciprofloxacin. On the other hand, SIgA generally increased the resistance of planktonic bacteria to ciprofloxacin, perhaps due in part to the SIgA-mediated aggregation of the bacteria. These findings suggest that incorporation of host-derived molecules into the extracellular matrix of symbiotic biofilms might profoundly alter the properties of those biofilms, including the resistance of those biofilms to antibiotics.

Gastroesophageal reflux-associated aspiration alters the immune response in asthma.

BACKGROUND: A large number of studies point toward chronic aspiration associated with gastroesophageal reflux disease (GERD) as an important factor involved in the development of asthma, the incidence of which has increased dramatically in industrially developed countries. Recent work suggests that medical intervention aimed at acid blockade is not sufficient to relieve the effects of chronic aspiration on asthma pathology, leaving surgical treatment of the disease as one of the few remaining options. This study examined the effect of chronic aspiration on the airway-associated immune response to allergens using a model of experimentally induced airway hypersensitivity in Balb/c mice. METHODS: The mice received aspiration of gastric fluid on days 1, 8, 15, 22, 29, 36, 43, and 50 and were sensitized to ovalbumin by intraperitoneal (IP) injection on days 33 and 47, challenged with aerosolized ovalbumin on day 54, and killed on day 56. Control mice received sham gastric fluid aspirations, sham induction of airway hypersensitivity, or both. RESULTS: Chronic aspiration of 50 microl murine gastric fluid once per week for 8 weeks had a profound effect on the immune system in the lung, with upregulation of the macrophage/monocyte-associated cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) and profound downregulation of a broad array of T-cell-associated cytokines including interleukins 2, 4, 5, 6, 10, 13, and 23, as well as interferon-gamma. The aspiration-induced depression of IL-5 production in particular was found only in mice with airway hypersensitivity and not in control mice without airway hypersensitivity. CONCLUSIONS: The results indicate that chronic aspiration of gastric fluid has a profound effect on the nature of the allergic response to aerosolized allergens, suggesting that the aspiration may be an important factor affecting the pathogenesis of asthma.

Improvement of active rheumatoid arthritis after etanercept injection: a single-center experience.

BACKGROUND: To study the clinical effectiveness and adverse reactions of etanercept in patients with active rheumatoid arthritis (RA), in whom combination therapies with disease-modifying antirheumatic drugs (DMARDs) had failed. METHODS: One hundred and thirty-three patients with active RA who had been treated without satisfactory effect with DMARDs were entitled, by the Taiwan Bureau of National Health Insurance, to undergo etanercept injection (25 mg subcutaneously, twice weekly) along with oral methotrexate (15 mg weekly) in Taipei Veterans General Hospital. The disease activity score in 28 swollen and 28 tender joints (DAS28), erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), rheumatoid factors (RFs), tender joint count (TJC), and swollen joint count (SJC) were recorded at the beginning, 3, 6, 9, and 12 months after treatment. Any adverse event, relevant or irrelevant to the therapy, was recorded throughout the whole course of treatment. RESULTS: Ninety-four patients completed the 1-year therapeutic program. There were significant improvements in all parameters (DAS28, ESR, CRP, TJC and SJC), which approached satisfactory values at the end of the first 3 months and which were sustained thereafter in most patients. Patients also tolerated the treatment protocol well, with adverse events occurring sporadically. Significant clinical response occurred as early as 3 months after the start and might last beyond 1 year in some patients. Adverse effects such as injection site reaction or infections rarely occurred. CONCLUSION: Combination therapy with etanercept and DMARDs seemed to be effective at improving the aching symptoms associated with rheumatoid activity and was well tolerated in this cohort study. It was generally safe, though a small number of non-fatal infections were observed.

Mycobacterium-associated lobular panniculitis, mimicking a rheumatoid nodule in a patient with rheumatoid arthritis.

Mycobacterium-associated lobular panniculitis can mimic a rheumatoid nodule and has been seldom reported in rheumatoid arthritis (RA). We describe a 69-year-old woman with RA who presented initially with fever and an indurated skin lesion on the right thigh. Lobular panniculitis was diagnosed after biopsy and was then treated with prednisolone. After this therapy, pulmonary infiltration developed and was later shown by transbronchial biopsy to be caused by Mycobacterium tuberculosis. The panniculitis skin lesion became smaller after prednisolone therapy and was further improved after antituberculosis drugs were added. Reexamination of the previously biopsied skin tissue disclosed acid-fast bacilli. Reactivation or new infection of M. tuberculosis is a current important issue in RA patients, especially after treatment with disease-modifying anti rheumatic drugs or antitumor necrosis factor agents. Mycobacterium-associated lobular panniculitis should be included in the differential diagnosis of indurated skin disorder in RA patients, and acid-fast staining or polymerase chain reaction examination of tuberculosis should be performed routinely on biopsied skin tissue.