Mechanisms of pleural involvement in orphan diseases

Over the past 10 years, the widespread clinical applicability of semi-invasive and noninvasive diagnostic tools including medical thoracoscopy and ultrasonography has expanded the occurrence of pleural effusions to include several rare diseases such as granulomatous, connective tissue and autoimmune disorders including sarcoidosis, granulomatosis with polyangiitis (Wegener's), systemic sclerosis, lupus erythematosus, rheumatoid arthritis, Sj?gren's syndrome, amyloidosis, Langerhans cell histiocytosis, and others. The purpose of this review is to summarize the current state of the knowledge regarding pathogenetic mechanisms of pleural involvement in rare disease entities and to highlight the need for more efforts to understand the underlying mechanisms for a more effective therapy.     

Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus

OBJECTIVE: To study the frequency and disease specificity of antinucleosome antibody reactivity in diverse connective tissue diseases (CTD), and to determine factors, such as antibody subclass, that may influence the pathogenicity of these antibodies in relation to disease activity. METHODS: IgG and IgM antinucleosome activities on nucleosome core particles from 496 patients with 13 different CTD and 100 patients with hepatitis C were measured by enzyme-linked immunosorbent assay (ELISA). Of the patients with CTD, 120 had systemic lupus erythematosus (SLE), 37 had scleroderma (systemic sclerosis; SSc), 20 had mixed connective tissue disease (MCTD), and 319 had other CTD, including Sj?gren's syndrome, inflammatory myopathy, rheumatoid arthritis, primary antiphospholipid syndrome, Wegener's granulomatosis, Takayasu arteritis, giant cell arteritis, relapsing polychondritis, Beh?et's syndrome, and sarcoidosis. Antinucleosome-positive sera were further analyzed, by isotype-specific ELISA, for antinucleosome and anti-double-stranded DNA (anti-dsDNA) IgG subclasses. RESULTS: SLE, SSc, and MCTD were the only 3 CTD in which antinucleosome IgG were detected (71.7%, 45.9%, and 45.0% of patients, respectively). Antinucleosomes of the IgG3 subclass were present at high levels in patients with active SLE and were virtually absent in those with SSc, MCTD, or inactive SLE, and their levels showed a positive correlation with SLE disease activity. Of note, an increase in levels of antinucleosome of the IgG3 isotype was observed during SLE flares, and this increase was found to be closely associated with active nephritis. Levels of antinucleosome of the IgG1 subclass showed a trend toward an inverse correlation with SLE disease activity. No significant fluctuation in the anti-dsDNA isotype profile was observed in relation to SLE severity or clinical signs. CONCLUSION: Our data suggest that IgG antinucleosome is a new marker that may help in the differential diagnosis of CTD; antinucleosome of the IgG3 isotype might constitute a selective biologic marker of active SLE, in particular, of lupus nephritis.     

Rheumatic manifestations of Behçet's disease

Rheumatologic manifestations are common in Beh?et's disease. Joint involvement takes the third place after mucocutaneous and ocular lesions and can be the inaugural manifestation. Monoarthritis and oligoarthritis affect essentially knees and ankles, with a marked male bias. They usually run an acute or recurrent course, with chronic forms being rare. Polyarthritis is not rare and involves the large limb joints and the small joints of the hands and feet. Arthritis in Beh?et's disease heels usually without sequelea and the aggressive treatment is not necessary. Unusual forms include arthritis with deformities and/or destruction, pseudogout, rupture of popliteal cyst (imitating deep vein thrombosis) and myositis. The association with spondylarthropathy is not common. Beh?et's disease is rarely associated with rheumatoid arthritis, Sj?gren's syndrome, systemic lupus erythematosus, relapsing polychondritis and amyloidosis. Children are more likely than adults to have joint manifestations and polyarthritis. CONCLUSION: Joint manifestations are common in Beh?et's disease. Their unusual forms deserve to be known since they can raise diagnostic problems when they are inaugural.     

Pulmonary manifestations of the collagen vascular diseases

The collagen vascular diseases are a heterogeneous group of immunologically mediated inflammatory disorders. The organs and tissues that compose the respiratory system are frequently affected by these diseases. Potential targets of the inflammation and injury include the lung parenchyma, tracheobronchial tree, pulmonary vasculature, pleura, larynx, and respiratory muscles. In this article, the spectrum of respiratory disease caused by systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis/dermatomyositis, mixed connective tissue disease, ankylosing spondylitis, relapsing polychondritis, and Sj?gren's syndrome is reviewed. Where appropriate, therapeutic options are discussed.     

Therapy insight: The recognition and treatment of retinal manifestations of systemic vasculitis

A variety of retinal signs can occur in patients who have systemic vasculitides, or who experience complications of these diseases or their treatment. Although treatment of these retinal manifestations is usually the treatment of the systemic disease, specific treatment is occasionally indicated to preserve vision. The more prevalent of the systemic vasculitides are giant cell arteritis, polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, relapsing polychondritis and systemic lupus erythematosus. Less frequently occurring vasculitides include Takayasu's arteritis, Goodpasture's disease, microscopic polyangiitis and Henoch-Sch?nlein purpura, as well as vasculitis secondary to scleroderma and rheumatoid arthritis. This article describes the pathogenesis, clinical features and treatment of retinal manifestations of systemic vasculitides.     

Inflammatory conditions of the eye associated with rheumatic diseases

Ocular inflammation occurs in many patients with systemic rheumatic disease. The best examples are rheumatoid arthritis, juvenile rheumatoid arthritis, temporal arteritis, systemic lupus erythematosus, Wegener’s granulomatosis, polyarteritis nodosa, relapsing polychondritis, and Adamantiades-Beh?et’s disease. Ocular inflammation may precede the symptoms of the systemic disease and can be helpful in systemic diagnosis. After diagnosis, ocular inflammation can mark the severity of the systemic condition. Thus, prompt diagnosis and treatment of inflammatory conditions of the eye are warranted and may be sight- and life-saving.     

The role of exercise in the rehabilitation of patients with systemic lupus erythematosus and patients with primary Sjögren's syndrome

PURPOSE OF REVIEW: The purpose of this review is to present an update on the evidence-based effects of exercise in systemic lupus erythematosus and in primary Sj?gren's syndrome. RECENT FINDINGS: Physical capacity is reduced in both systemic lupus erythematosus and primary Sj?gren's syndrome and fatigue is a dominating and disabling symptom in both conditions. The documentation on the effect of exercise on the rehabilitation of patients with systemic lupus erythematosus and primary Sj?gren's syndrome is sparse; the studies are few and the sample sizes often small. The available studies indicate that patients with systemic lupus erythematosus of mild to moderate disease activity as well as patients with primary Sj?gren's syndrome benefit from exercise of moderate to high intensity. Positive effects can be expected with regard to aerobic capacity, fatigue, physical function and depression. SUMMARY: There is reason to believe that exercise should be included in the rehabilitation of patients with mild to moderate systemic lupus erythematosus and patients with primary Sj?gren's syndrome. Further research is needed and should aim to evaluate the effect of exercise on groups with varying degree of disease severity and to document the long-term impact on the disease.     

Subclinical alveolitis in immunological systemic disorders. Transition between health and disease?

A subclinical inflammatory alveolitis as assessed by BAL cell analysis may be present in a high proportion of symptomless patients with immunological systemic disorders and with normal chest roentgenogram. Subclinical alveolitis can be characterized by the relative proportions of the different cell populations comprising the alveolitis and by the activated state of the cells. Thus, subclinical alveolitis can be classified into two major groups: lymphocyte and neutrophil alveolitis. Lymphocyte alveolitis is frequently found in patients with extrathoracic granulomatosis (Crohn's disease, primary biliary cirrhosis, extrathoracic sarcoidosis) or with some collagen vascular diseases (Sj?gren's syndrome, rheumatoid arthritis, systemic lupus erythematosus). Neutrophil alveolitis is a main finding in collagen vascular diseases, especially progressive systemic sclerosis, dermatopolymyositis and mixed connective tissue disease. In addition, alveolar macrophages may be spontaneously activated and release various mediators that could be relevant to the pathogenesis of interstitial lung disease. On the other hand, some other alveolar macrophage functions (antibacterial activity may be severely impaired in some diseases, for example systemic lupus erythematosus). Alveolar inflammation is associated with an increase in the permeability of the alveolar membrane responsible for an increased influx of blood proteins in the alveolar spaces. Although subclinical inflammation may also be detected by high resolution computed tomography (HRCT) scan and/or lung permeability scintigraphic studies, the significance and prognostic value remains unclear and clearly differs according to both the disease and the pattern of alveolitis.     

Sarcoidosis in autoimmune disease.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Sarcoidosis coexisting with connective tissue diseases, once considered rare, complicates various such disorders, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sj?gren's syndrome, and the spondyloarthropathies. Symptoms common to sarcoidosis and autoimmune disease include keratoconjunctivitis sicca, weight loss, fever, lymphadenopathy, pulmonary complaints, and cutaneous lesions. Consequently, the diagnosis of sarcoidosis in association with connective tissue disease is often difficult and may require biopsy of the lung, liver, skin, lymph node, muscle, or bone marrow for pathological confirmation. Abnormalities of immune function as well as autoantibody production, including rheumatoid factor and antinuclear antibodies, are seen in sarcoidosis and in connective tissue diseases, suggesting a common immunopathogenic mechanism. The severity and course of sarcoidosis associated with autoimmune disease is variable. The incidence of sarcoidosis in association with rheumatic disease may be underestimated if new symptoms of sarcoidosis are attributed to the primary rheumatic disease and a secondary diagnosis is not pursued.     

Familial occurrence of systemic sclerosis, rheumatoid arthritis and other immunological disorders: report of two kindreds with study of HLA antigens and review of the literature

We report two Caucasian families with systemic sclerosis and other connective tissue and immunological disorders, including rheumatoid arthritis, discoid lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, asthma, Sj?gren's syndrome, Raynaud's phenomenon and thyroid disease. In one of these families, two sisters are affected with systemic sclerosis. Clinical, serological, and HLA haplotype results are reported, along with a review of the medical literature on familial occurrence of systemic sclerosis.     

Anti-chromatin and anti-C1q antibodies in systemic lupus erythematosus compared to other systemic autoimmune diseases

OBJECTIVE: To evaluate the prevalence, sensitivity, and specificity of anti-chromatin and anti-C1q antibodies in systemic lupus erythematosus (SLE) and lupus nephritis compared to small vessel vasculitis and other connective tissue diseases. To provide long-term follow-up data for anti-chromatin antibodies in lupus nephritis. METHODS: We determined the significance of anti-nuclear antibodies (ANA), anti- double-stranded DNA (anti-dsDNA), anti-chromatin, and anti-C1q antibodies, as well as complement factors C3 and C4, in relation to disease activity in SLE patients with (n = 47; long-term follow-up data for 33 patients) and without (n = 31) biopsy-confirmed lupus nephritis, microscopic polyangiitis (n = 37), Wegener's granulomatosis (n = 66), primary Sj?gren's syndrome (n = 17), limited scleroderma (CREST syndrome) (n = 6), and progressive systemic scleroderma (PSS) (n = 11). RESULTS: Anti-chromatin antibodies were more specific and sensitive than anti-C1q antibodies in distinguishing SLE patients from those with other systemic autoimmune diseases [anti-chromatin: sensitivity 64.1%, specificity 99.2%, odds ratio (OR) 219.6; anti-C1q: sensitivity 50%, specificity 72.6%, OR 2.65]. Anti-C1q antibodies were present in 75% of patients with Sj?gren's syndrome and 35.1% of patients with microscopic polyangiitis. Anti-chromatin antibodies could identify SLE in patients with positive ANA but negative anti-dsDNA antibodies. Persisting anti-chromatin antibodies indicated SLE disease activity, even if anti-dsDNA antibodies had become negative. In long-term follow-up, those SLE patients with negative anti-dsDNA antibodies but persisting ANA and anti-chromatin antibodies relapsed if immunosuppression had been tapered. Anti-chromatin antibodies correlated with the SLE disease activity index (SLEDAI) as a marker of disease activity. CONCLUSIONS: The measurement of anti-chromatin, but not anti-C1q, antibodies in patients with systemic autoimmune diseases increases diagnostic sensitivity and specificity for SLE and assists in treatment decisions in anti-dsDNA-negative patients.     

Relationship of Sjögren's syndrome to other connective tissue and autoimmune disorders

Sj?gren's syndrome is a systemic autoimmune disease that frequently presents concomitantly with other systemic connective tissue or organ-specific autoimmune diseases. This association is well described for systemic lupus erythematosus and rheumatoid arthritis. The presence of Sj?gren's syndrome influences the expression of the other autoimmune disease to some degree, for instance by increasing fatigue and lymphoma risk. The etiopathogenic mechanism for the simultaneous or sequential development of multiple autoimmune diseases in one individual is not well understood. Common genetic backgrounds and additional immunogenetic, environmental, or hormonal factors may be responsible for the formation of subsets of autoimmune disease clustering. While the most currently accepted classification criteria (American European Consensus Criteria) designate these cases as secondary Sj?grens syndrome, the terms overlapping or associated Sj?gren's syndrome are frequently used in the literature to describe these cases.     

Laboratory diagnostics of systemic autoimmune diseases. Part 1. Collagenoses

This is the first part of a series of articles on the laboratory diagnostics of rheumatic diseases and will consider the systemic autoimmune diseases lupus erythematosus, Sj?gren's syndrome, systemic sclerosis, dermato/polymyositis and mixed connective tissue disease (MCTD, SHARP syndrome). The basis for diagnostics is the presence of antinuclear antibodies (ANA). Initially, these antibodies are detected using a screening test. This must be followed by the identification of the patient's individual autoantibody specificities, which then yields important diagnostic clues. Disease activity may be monitored serologically by following the titers of selected autoantibodies and, in certain patients, by examining complement consumption.     

Rare autoimmune rheumatic illnesses during pregnancy. Systemic sclerosis, polymyositis/dermatomyositis and vasculitis

Autoimmune rheumatic diseases (ARD) affect young females during childbearing age. Over the last decades, improvements in survival as well as quality of life in patients affected with ARD have led to an increased number of pregnancies observed during the course of such diseases. Systemic lupus erythematosus (SLE) is the most frequently observed ARD during pregnancy, and the immunoendocrine changes occurring during pregnancy may influence the course of this disease. Pregnancy can also occur in patients with rare ARD, namely systemic sclerosis, polymyositis/dermatomyositis, systemic vasculitis including Wegener's granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyangiitis, Takayasu arteritis and Beh?et disease. This review focuses on the complications during pregnancy caused by these rare ARD, and we briefly discuss the data published on these disorders. Some guidelines for the management of these conditions during pregnancy will also be provided. However, it is important to note that data on pregnancy outcome are very limited and, in the absence of prospective studies, most of the information derives from case reports and retrospective studies.     

Coexisting relapsing polychondritis and sarcoidosis: an unusual association

Relapsing polychondritis is an episodic and progressive systemic inflammatory disease characterized by auricular chondritis, polyarthritis, nasal and respiratory tract chondritis. About 30% of the patients have additional autoimmune and or hematological diseases, most frequently systemic vasculitis, rheumatoid arthritis, myelodysplastic syndromes or systemic lupus erythematosus. So far, only one case of coexisting relapsing polychondritis and sarcoidosis in a patient with AIDS has been reported. We describe here a case of sarcoidosis and relapsing polychondritis in an immunocompetent patient. Physicians should be aware of this possible association.     

Acquired immunodeficiency syndrome mimicking Sj?gren's syndrome and systemic lupus erythematosus

We describe a patient in whom the diagnosis of transfusion-associated acquired immunodeficiency syndrome (AIDS) was delayed because her clinical symptoms were similar to those of systemic lupus erythematosus and Sj?gren's syndrome and because of a false-negative result on a Western blot test for human immunodeficiency virus. The importance of using different diagnostic tests for AIDS and the pitfalls in diagnosing AIDS in patients who appear to have connective tissue disease are discussed.     

The lung as a reflection of internal medicine diseases]

The lungs are called "mirror of internal medicine" because they are often involved in multisystem diseases. The morphologic changes of the lungs are uncharacteristic and the classification is only possible in relation to other manifestations of multisystem diseases. In this article clinical syndromes with pulmonary manifestations will be reviewed. Congestive heart failure and congenital diseases may lead to pulmonary features. Most cardial pleural effusions are transudates except postcardiac injury syndrome causes pleural exsudates. Almost all connective tissue diseases may affect the lungs and the pleura. Scleroderma, systemic lupus erythematodes, vasculitis, polymyositis, Sharp's syndrome, Wegener's granulomatosis, Goodpasture and Sj?gren's syndrome, rheumatoid arthritis, ankylosing spondylitis and sarcoidosis are discussed. There is an association of gastroesophageal reflux and asthma. Acute pancreatitis may cause an adult respiratory distress syndrome. Endocrine and hematologic diseases seldom cause pulmonary changes. Many malignant tumors are going along with metastasis in the lungs. Renal insufficiency causes "fluid lung", nephrotic syndrome pleural effusions. Finally different drugs induce pulmonary diseases.     

肿瘤坏死因子抑制剂在指征外自身免疫性疾病中的应用

肿瘤坏死因子(tumor necrosis factor-alpha,TNF-α)介导的免疫反应在众多自身免疫性疾病的发病中均具有重要的作用。通过PubMed及中国知网(CNKI,2001-2009年)检索并综合统计,发现除了FDA批准的适应证外,TNF-α抑制剂在多种自身免疫性疾病中都有指征外应用,国外文献中有9个随机对照试验,国内文献只有依那西普治疗贝赫切特病(白塞病)的两篇病例报告。综合文献结果,提示英夫利昔单抗对贝赫切特病、系统性红斑狼疮、结节病治疗有效,不推荐应用于干燥综合征、新发巨细胞动脉炎和风湿性多肌痛;依那西普对贝赫切特病有效,不推荐应用于干燥综合征、韦格纳肉芽肿和结节病。目前临床证据主要基于无对照的临床研究及个案报道,以上结论有待大规模随机对照试验进一步证实。     

Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature

In adults, the term specific pulmonary renal syndrome describes disorders with pulmonary and glomerular manifestations and includes Wegener's granulomatosis, Goodpasture disease, and systemic lupus erythematosus. Nonspecific pulmonary renal syndrome refers to either pulmonary disease complicating glomerular disease, or glomerular diseases following pulmonary disease. Since little is known regarding pulmonary renal syndrome in childhood, we reviewed the charts of 21 pediatric patients with pulmonary renal syndromes treated by the Department of Pediatrics, University of Bern between 1991 and 1998; we also reviewed the pediatric literature that deals with specific pulmonary renal syndromes. Specific pulmonary renal syndrome was noted in 3 children with systemic vasculitis (Wegener granulomatosis, N = 2; microscopic polyangiitis, N = 1) and 2 with systemic lupus erythematosus. Nonspecific pulmonary renal syndrome was observed in 12 patients with pulmonary edema (N = 9), pulmonary thromboembolism (N = 2), and pulmonary infection (N = 1) complicating the course of a glomerular disease, and in 4 children with a pulmonary disease followed by a glomerular disease. Review of the literature disclosed 52 cases of specific pulmonary renal syndrome other than systemic lupus erythematosus: Wegener granulomatosis (N = 28), Goodpasture disease (N = 13), and Henoch-Sch?nlein purpura (N = 11). In addition, hemolytic uremic syndrome complicated pneumococcal pneumonia in 32 cases. We conclude that pulmonary renal syndromes need to be looked for in childhood. Apart from Wegener granulomatosis, Goodpasture disease, and systemic lupus erythematosus, Henoch-Sch?nlein purpura and hemolytic-uremic syndrome occasionally have both pulmonary and renal features.     

The molecular genetics of systemic lupus erythematosus and Sj?gren's syndrome.

Refinements in molecular genetic technology as well as in the organization of the major histocompatibility complex and the genes contained therein continue to lead the way to elucidation of the immunogenetics of systemic lupus erythematosus and Sj?gren's syndrome. In this article, recent advances in these areas are reviewed, and major histocompatibility complex associations with systemic lupus erythematosus and Sj?gren's syndrome will be explored with particular emphasis on autoantibody subsets of these diseases. Data thus far support the hypothesis that systemic lupus erythematosus and Sj?gren's syndrome are clinically and serologically heterogeneous disorders of major histocompatibility complex class II allele-associated autoantibody subsets, to which other major histocompatibility complex genes (C4 null alleles) and non-major histocompatibility complex genes (such as T-cell receptor genes) may contribute in susceptibility.