Vasculitis in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex heterogeneous autoimmune disease with a wide variety of clinical and serological manifestations that may affect any organ. Vasculitis prevalence in SLE is reported to be between 11 % and 36 %. A diverse clinical spectrum, due to inflammatory involvement of vessels of all sizes, is present. Even though cutaneous lesions, representing small vessel involvement, are the most frequent, medium and large vessel vasculitis may present with visceral affection, with life-threatening manifestations such as mesenteric vasculitis, pulmonary hemorrhage, or mononeuritis multiplex, with detrimental consequences. Early recognition and an appropriate treatment are crucial. Recent studies have shown that vasculitis in patients with SLE may present different clinical forms based on the organ involved and the size of the affected vessel. It is noteworthy that the episodes of vasculitis are not always accompanied by high disease activity. Recent articles on this topic have focused on new treatments for the control of vascular disease, such as biological therapies such as Rituximab and Belimumab, among others.     

Pulmonary manifestations of inflammatory bowel disease

Extraintestinal manifestations of both Crohn's disease and ulcerative colitis (UC) have been well described, although pulmonary findings are often overlooked. We summarize the experience of more than 400 cases of pulmonary manifestations of inflammatory bowel disease (IBD). These manifestations will be categorized by disease mechanism into drug-induced disease, anatomic disease, over-lap syndromes, autoimmune disease, physiologic consequences of IBD, pulmonary function test abnormalities, and nonspecific lung disease. We intend to provide the clinician with a practical working update on the spectrum of pulmonary dysfunction associated with IBD.     

Is it SLE?

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease, as yet of unknown aetiology, with diverse clinical manifestations and a variable course and prognosis. The diagnosis is based on recognizing the overall pattern of clinical and laboratory abnormalities. However, even today, there is often a significant delay between onset of symptoms and diagnosis. Over the last two decades there has been great progress in identifying the profile of antinuclear antibodies that characterizes SLE, and in this chapter we describe how serological techniques can be important tools for the clinician in the early diagnosis of this disorder. Also described is the lupus band test, which has rather fallen out of favour as a diagnostic tool but which can still provide valuable evidence for the diagnosis in patients in whom the clinical and serological features are inconclusive. Nevertheless, because the presentation of lupus is protean, and the early manifestations are often non-specific, SLE can still be easily confused with a wide range of other conditions. Here, we describe some of the common clinical conundrums encountered in patients referred to the Lupus Clinic to 'rule out lupus', providing a framework for diagnosis. Finally, the chapter considers the major problem that clinicians who treat patients with SLE frequently face in distinguishing between a flare of lupus and infection. Diagnosis of SLE is still a great clinical challenge, and while it is important to recognize patients with potentially aggressive disease and treat them appropriately at an early stage it is also important to be able to recognize patients with potentially benign disease and avoid over-treatment.     

Skin manifestations of systemic autoimmune connective tissue disease: diagnostics and therapeutics

Skin disease can significantly affect the quality of life of patients suffering from rheumatic diseases. In addition, important relationships exist between the cutaneous and systemic manifestations of rheumatic disease. It is thus important for practicing rheumatologists to have a solid working understanding of the subject of rheumatic skin disease. Unfortunately, it is not possible within the scope of this chapter to provide a comprehensive overview of the recognition and management of all of the cutaneous manifestations of lupus erythematosus (LE), much less those of dermatomyositis (DM)/polymyositis and scleroderma/systemic sclerosis (SSc) as well. As can be seen in in the text, the cutaneous manifestations of polygenic autoimmune disorders such as LE can be as heterogeneous clinically as are its systemic manifestations. This discussion will therefore focus on recent key developments concerning the diagnosis and management of the more common skin changes that the practicing rheumatologist is likely to encountered in the three major rheumatic diseases: LE, DM and SSc.     

Clinical manifestations and treatment of antisynthetase syndrome

Antisynthetase syndrome (ASyS) is an autoimmune disease clinically manifested most often by interstitial lung disease, myositis, and arthritis. Raynaud's syndrome, fever, and rashes are also commonly seen. This syndrome is characterized by the highly specific presence of antibodies against various aminoacyl transfer RNA synthetases, including Jo-1 and others. In this chapter, we provide an overview of ASyS, including pathogenesis, common clinical manifestations, and treatment strategies. We discuss the spectrum of disease seen with specific antisynthetase antibodies and examine the differences in phenotype between patients with different antisynthetase antibodies. We outline common treatment strategies, which should generally target the most severe and life- or organ-threatening disease manifestations. Finally, we discuss short- and long-term prognosis in ASyS.     

Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment

Non-classical manifestations of autoimmune hepatitis can delay diagnosis and treatment. Our aims were to describe the clinical phenotypes that can confound the diagnosis, detail scoring systems that can ensure their recognition, and outline advances in treatment that can improve their outcome. Prime source and review articles in English were selected throuqh Medline from 1970-2008 and assimilated into personal libraries spanning 32 years. Acute severe or asymptomatic presentations and atypical histological findings,including centrilobular zone 3 necrosis and concurrent bile duct changes, are compatible with the diagnosis. Cholangiographic abnormalities may be present in children and adults with the disease, and autoimmune hepatitis must be considered in patients without autoantibodies or with antimitochondrial antibodies and no other cholestatic features. Asymptomatic patients frequently become symptomatic; mild disease can progress; and there are no confident indices that justify withholding treatment. Two diagnostic scoring systems with complementary virtues have been developed to evaluate patients with confusing features. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long- term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies,and budesonide with azathioprine may be a superior frontline treatment. We conclude that the non-classical phenotypes of autoimmune hepatitis can be recognized promptly, diagnosed accurately, and treated effectively.     

Unusual radiologic manifestations of the echinococcus infection in the thorax

Unusual location and presentation of hydatid cyst disease in the thorax requires careful consideration with respect to clinical approach and therapy. In this pictorial essay, we present imaging findings and describe treatment of thoracic hydatid cysts in patients with lung, mediastinal, chest wall, cardiac, endobronchial, pulmonary artery, and diaphragmatic involvement. A review of the literature is also included.     

Autoimmune Pankreatitis

Autoimmune pancreatitis has been established as a special entity of pancreatitis. It is an enigmatic disease since it is adding an autoimmune etiology to the existing causes of pancreatitis. Morphological hallmarks of the disease are narrowing of the pancreatic duct system and the bile duct by periductal lymphoplasmocytic inflammation. This results in many cases in obstructive jaundice due to a mass-forming lesion in the pancreatic head mimicking pancreatic ductal adenocarcinoma. Therefore, patients will frequently undergo surgery. Histopathologically, the disease can be diagnosed by IgG4-positive plasma cells. Serologically, patients may present with elevated serum IgG and IgG4 levels. Other autoantibodies are also described. Association with other autoimmune manifestations in a wide range of organs is frequent. Autoimmune pancreatitis will respond to steroid treatment, which is of specific importance because pancreatic cancer is one of its clinical differential diagnoses. It is important to positively diagnose autoimmune pancreatitis, especially if the bile ducts are affected, since cholangitis may be or become a prominent problem before or after surgery.     

Clinical and radiological characteristics of lung disease in inflammatory bowel disease.

The pulmonary associations of inflammatory bowel disease (IBD) are poorly characterized. The clinical, physiological and high-resolution computed tomographic thorax characteristics of the lung disease in patients with IBD presenting with respiratory symptoms are described. Detailed clinical information was obtained and standard pulmonary physiological tests and thorax high-resolution computed tomography performed on 14 patients with ulcerative colitis (UC) and three with Crohn's disease (CD), 10 male, aged 38-83 yrs. Respiratory symptoms had been present for 2-50 yrs and extraintestinal manifestations were present in three (17.6%). Normal pulmonary physiology (six patients) was associated with the high resolution computed tomographic changes of bronchiectasis, mosaic perfusion and air trapping suggestive of obliterative bronchiolitis and a pattern of centrilobular nodules and branching linear opacities ("tree in bud" appearance) suggestive of either cellular bronchiolitis or bronchiolectasis with mucoid secretions. Bronchiectasis was found in 13 patients (11 UC, 2 CD), 11 had air trapping and five had a "tree in bud" appearance on computed tomography. One patient had a predominantly peripheral reticular pattern at the lung bases similar to that found in cryptogenic fibrosing alveolitis and one patient had a mixed reticular and ground-glass pattern in the midzones with a patchy distribution in the central and peripheral portions of the lungs with air trapping. Eleven patients (three with alveolitis) exhibited a clinical and/or physiological response to steroids. Pulmonary abnormalities in ulcerative colitis and Crohn's disease can present years after the onset of the bowel disease and can affect any part of the lungs. Early recognition is important as they can be strikingly steroid-responsive.     

Autosomal recessive chronic granulomatous disease, IgA deficiency and refractory autoimmune thrombocytopenia responding to Anti-CD20 monoclonal antibody

Immunodeficiency and autoimmune disease may occur concomitantly in the same individual. Some of the immunodeficiency syndromes, especially humoral defects are associated with autoimmune disorders. Hematological manifestations such as thrombocytopenia and hemolytic anemia are the most common presentations. Persistent antigen stimulation due to an inherent defect in the ability of the immune system to eradicate pathogens is the primary cause leading to autoimmunity in patients with primary immunodeficiency states.We describe a 10 year old Iranian girl with chronic granulomatous disease -the autosomal recessive type with mutation of NCF1 gene P47- associated with selective IgA deficiency, refractory immune thrombocytopenia that showed an excellent response to Rituximab (Anti-CD20 monoclonal antibody).Patients with primary immunodeficiencies may have variable autoimmune manifestations. So for early detection and appropriate treatment, autoimmune diseases should always be suspected in such patients.     

Extraintestinal manifestations of Crohn's disease

In each case of extraintestinal manifestations of Crohn's disease, active disease, if present, should be treated to induce remission, which may positively influence the course of most concomitant extraintestinal manifestations. For some extraintestinal manifestations, however, a specific treatment should be introduced. This latter part of disease management will be discussed in this chapter, in particular for pyoderma gangrenosum, uveitis, spondylarthropathy - axial arthropathy - and primary sclerosing cholangitis, which have also been described in quiescent Crohn's disease. Few new drugs for the treatment of extraintestinal manifestations of Crohn's disease have been developed in the past and only the role of infliximab has increased in Crohn's disease-related extraintestinal manifestations. Drugs specifically aimed at this treatment, stemming from a few randomized controlled studies or case series, are sulfasalazine, 5-ASA, corticosteroids, azathioprine or 6-mercaptopurine, methotrexate, infliximab, adalimumab, etanercept and cyclosporine or tacrolimus. Unfortunately, because of the paucity of data in this field, the best evidence presented and discussed in this article for the treatment of these extraintestinal manifestations is extrapolated from patients that for the most part did not suffer from Crohn's disease.     

Treatment of idiopathic pulmonary fibrosis: a position paper from a Nordic expert group

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the updated disease classification have been published. The registration of pirfenidone and nintedanib, the first two pharmacological treatment options approved for IPF, marks a new chapter in the management of patients with this disease. Other nonpharmacological treatments such as lung transplantation, rehabilitation and palliation have also been shown to be beneficial for these patients. In this review, past and present management is discussed based on a comprehensive literature search. A treatment algorithm is presented based on available evidence and our overall clinical experience. In addition, unmet needs with regard to treatment are highlighted and discussed. We describe the development of various treatment options for IPF from the first consensus to recent guidelines based on evidence from large‐scale, multinational, randomized clinical trials, which have led to registration of the first drugs for IPF.     

Complex management issues: management of HCV in the atypical patient.

Some patients with chronic hepatitis C virus (HCV) infection demonstrate atypical features of presentation and clinical course. These features may be due to direct or indirect effects of the underlying HCV infection or may be part of a separate clinical syndrome. Patients that can be categorized as 'atypical' include immunosuppressed individuals (hypogammaglobulinaemic, co-infected with human immunodeficiency virus, recipients of solid organ or haematopoietic cell transplants, those with associated disease requiring chronic immunosuppressive therapy and patients with chronic renal failure on haemodialysis) as well as patients with various extra-hepatic (HCV-associated mixed cryoglobulinaemia, membranoproliferative glomerulonephritis etc) or autoimmune manifestations. Since many of these patients have been excluded from the large trials evaluating the efficacy of interferon-alpha alone or in combination with ribavirin, data regarding management are limited. In this chapter, the available information regarding the treatment of these patients is reviewed and the frequently encountered therapeutic dilemmas discussed. Finally, some reasonable therapeutic approaches are suggested while the need for controlled studies for these groups of patients is emphasized.     

How to manage patients with cardiopulmonary disease?

Systemic lupus erythematosus (SLE) is a connective tissue disease characterized by the formation of autoantibodies and immune complexes. The heart and lungs are among the organ systems commonly affected in SLE. Pericarditis, premature coronary atherosclerosis, pleuritis and pulmonary infections are the most prevalent cardiopulmonary manifestations. Other rare associations include myocarditis, coronary arteritis, acute lupus pneumonitis/pulmonary haemorrhage, acute reversible hypoxaemia and 'shrinking lung' syndrome. Current imaging modalities may provide earlier detection of subclinical disease, which may aid in preventing these potentially fatal complications. The response to treatment varies, depending on the presentation of disease. In this chapter we address the frequency, diagnosis and monitoring, and treatment regimens of cardiac and pulmonary involvement in patients with SLE.     

Extraintestinal manifestations of Crohn's disease

In each case of extraintestinal manifestations of Crohn's disease, active disease, if present, should be treated to induce remission, which may positively influence the course of most concomitant extraintestinal manifestations. For some extraintestinal manifestations, however, a specific treatment should be introduced. This latter part of disease management will be discussed in this chapter, in particular for pyoderma gangrenosum, uveitis, spondylarthropathy--axial arthropathy--and primarysclerosing cholangitis, which have also been described in quiescent Crohn's disease. Few new drugs for the treatment of extraintestinal manifestations of Crohn's disease have been developed in the past and only the role of infliximab has increased in Crohn's disease-related extraintestinal manifestations. Drugs specifically aimed at this treatment, stemming from a few randomized controlled studies or case series, are sulfasalazine, 5-ASA, corticosteroids, azathioprine or 6-mercaptopurine, methotrexate, infliximab, dapsone and cyclosporine or tacrolimus.     

Irradiation damage to the lung

While some degree of injury to normal, non-tumor-bearing, intrathoracic structures always occurs following irradiation for cure or palliation of neoplastic disease, clinical expression of this injury is uncommon. However, under certain circumstances, clinical manifestations may be severe and life threatening. Acute radiographic manifestations of pulmonary injury usually appear either synchronous with or, more typically, seven to ten days after the onset of the clinical syndrome. The acute signs of edema and slight volume loss within the irradiated zone are nonspecific except for their temporal and spatial relationship to the irradiation of the patient. Resolution of the acute changes is followed by pulmonary cicatrization, which is almost always stable within one year after completion of therapy. Change in postirradiation scarring following stabilization of the reaction must always be assumed to be due to some other process. While the radiograph primarily reveals pulmonary injury, all tissues, including the heart and major vessels, are susceptible, and the radiologist must recognize that any change within the thorax of a patient who has undergone thoracic irradiation may be a complication of that treatment. Differentiation of irradiation injury from residual or recurrent tumor, drug reaction, or opportunistic infection may be difficult and at times impossible.     

Systemic lupus erythematosus following virological response to peginterferon alfa-2b in a transplanted patient with chronic hepatitis C recurrence

Autoimmune manifestations are common both in patients chronically infected by hepatitis C virus, and in patients transplanted for non-autoimmune diseases. A correlation between interferon based treatment and autoimmune diseases or the development of autoantibodies is well established in non-transplanted patients, but few data are available about transplanted patients. It is unclear whether interferon may increase the incidence of acute cellular rejection and there are few reports on the development of atypical autoimmune manifestations during post-liver transplantation interferon or pegylated interferon treatment. We describe a case of systemic lupus erythematosus following treatment with pegylated interferon alfa-2b in a transplanted patient with recurrence of chronic hepatitis C. Our experience suggest that pegylated interferon may induce autoimmune diseases in the immunosuppressed host, different from acute cellular rejection and call for a great attention to possible autoimmune disorders development during interferon based treatments in liver transplanted patients.     

The spectrum of lung involvement in collagen vascular-like diseases following allogeneic hematopoietic stem cell transplantation: report of 6 cases and review of the literature

Multisystem autoimmune diseases occurring after allogeneic hematopoietic stem cell transplantation are infrequent, late-onset manifestations that resemble well-defined collagen vascular disorders. Because the lung is frequently involved in the course of connective tissue disorders, we focused on lung manifestations occurring in autoimmune diseases following allogeneic stem cell transplantation. In the present series, we report 6 patients with systemic lupus erythematous, mixed connective tissue disease, Sj?gren syndrome, polymyositis, and ANCA-positive vasculitis who presented with a spectrum of pulmonary manifestations affecting the airways, lung parenchyma, and probably respiratory muscles. We identified 3 different histopathologic patterns of interstitial pneumonia consistent with the underlying autoimmune disorder: lymphocytic interstitial pneumonia and non-specific interstitial pneumonia in 2 patients with Sj?gren syndrome and diffuse alveolar damage in 1 patient with ANCA-positive vasculitis. These lung manifestations had poor prognoses. Further studies are needed to determine the optimal therapy for these complications.     

Treating severe systemic lupus erythematosus with rituximab. An open study

Systemic lupus erythematosus (SLE) is an autoimmune disease that may be associated to high morbidity and mortality. Disease course is variable and unpredictable and although the prognosis and survival of these patients has dramatically improved, treatment of severe multiorganic organic affection in this condition remains a therapeutic challenge. Since B lymphocytes have an important role in the pathogenesis of SLE, it is expected that the targeting of these cells exerts a significant therapeutic effect in SLE patients with severe multiorganic manifestations. In an open clinical trial, we have explored the therapeutic potential of Rituximab (an anti-CD20 monoclonal antibody) administration in SLE patients with severe nephritis (n=22) or neuropsychiatric manifestations (n=6) or massive pulmonary hemorrhage (n=3). In most cases, we observed significant improvement in both clinical and laboratory parameters, with good tolerance and few side effects. Thus, patients with severe lupus nephritis showed improvement in disease activity (MEX-SLEDAI index) with a significant reduction (p<0.05), as well as proteinuria in most of them (from 3.710g/L to 1.786g/L, p<0.05); patients with serious neurologic involvement had complete remission of their manifestations; but those with pulmonary massive hemorrhage did not have any response. Rituximab could have an important therapeutic potential in severe SLE, and that it is necessary to carry out a controlled blinded clinical trial to further support this point.