Anupama Shahane

Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis

The focus of this review is to increase awareness of pulmonary arterial hypertension (PAH) in patients with rheumatic diseases. Epidemiology and pathogenesis of PAH in rheumatic diseases is reviewed, with recommendations for early screening and diagnosis and suggestion of possible role of immunosuppressive therapy in treatment for PAH in rheumatic diseases. A MEDLINE search for articles published between January 1970 and June 2012 was conducted using the following keywords: pulmonary hypertension, scleroderma, systemic sclerosis, pulmonary arterial hypertension, connective tissues disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren’s syndrome, vasculitis, sarcoidosis, inflammatory myopathies, dermatomyositis, ankylosing spondylitis, spondyloarthropathies, diagnosis and treatment. Pathogenesis and disease burden of PAH in rheumatic diseases was highlighted, with emphasis on early consideration and workup of PAH. Screening recommendations and treatment were touched upon. PAH is most commonly seen in systemic sclerosis and may be seen in isolation or in association with interstitial lung disease. Several pathophysiologic processes have been identified including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi and pulmonary fibrosis. PAH in systemic lupus erythematosus is associated with higher prevalence of antiphospholipid and anticardiolipin antibodies and the presence of Raynaud’s phenomenon. Endothelial proliferation with vascular remodeling, abnormal coagulation with thrombus formation and immune-mediated vasculopathy are the postulated mechanisms. Improvement with immunosuppressive medications has been reported. Pulmonary fibrosis, extrinsic compression of pulmonary arteries and granulomatous vasculitis have been reported in patients with sarcoidosis. Intimal and medial hyperplasia with luminal narrowing has been observed in Sjogren’s syndrome, mixed connective tissue disease and inflammatory myopathies. Pulmonary arterial hypertension (PAH) associated with rheumatic diseases carries a particularly grim prognosis with faster progression of disease and poor response to therapy. Though largely associated with systemic sclerosis, it is being increasingly recognized in other rheumatic diseases. An underlying inflammatory component may explain the poor response to therapy in patients with rheumatic diseases and is a rationale for consideration of immunosuppressive therapy in conjunction with vasodilator therapy in treatment for PAH. Further studies identifying pathogenetic pathways and possible targets of therapy, especially the role of immunomodulatory medications, are warranted.

Do Bugs Control Our Fate? The Influence of the Microbiome on Autoimmunity

Autoimmune disease has traditionally been thought to be due to the impact of environmental factors on genetically susceptible individuals causing immune dysregulation and loss of tolerance. However, recent literature has highlighted the importance of the microbiome, (a collective genome of microorganisms in a given niche) in immune homeostasis. Increasingly, it has been recognized that disruptions in the commensal microflora may lead to immune dysfunction and autoimmunity. This review summarizes recent studies investigating the interplay between the microbiome and immune-mediated organ-specific diseases. In particular, we review new findings on the role of the microbiome in inflammatory bowel disease, celiac disease, psoriasis, rheumatoid arthritis, type I diabetes, and multiple sclerosis.

Interstitial Lung Disease in Systemic Sclerosis: Pathophysiology, Current and New Advances in Therapy

Systemic sclerosis is an autoimmune connective tissue disorder characterized by fibrosis of the skin and visceral organs. Interstitial lung disease (ILD) is a major complication of this disease and along with pulmonary arterial hypertension is the leading cause of mortality in scleroderma patients. The pathogenesis of pulmonary fibrosis is characterized by epithelial cell injury, activation of the coagulation pathway and inflammation, which create a profibrogenic environment in the lung in the setting of autoimmunity. The current standard of treatment for ILD in systemic sclerosis is cyclophosphamide. In view of the modest benefits in pulmonary function seen with cyclophosphamide in two recent trials and its significant toxicity, the search for alternative treatments is ongoing. With the advances in our understanding of the pathogenic mechanisms of pulmonary fibrosis, many promising therapeutic agents have come into view, but their efficacy needs to be evaluated before they can be recommended clinically. This review discusses the pathogenesis of pulmonary fibrosis with a focus on the potential target pathways, the current treatment options and recent advances in the treatment of ILD in systemic sclerosis.

Immune Reconstitution Inflammatory Syndrome Associated with Biologic Therapy

The use of biologics in the treatment of autoimmune disease, cancer, and other immune conditions has revolutionized medical care in these areas. However, there are drawbacks to the use of these medications including increased susceptibility to opportunistic infections. One unforeseen risk once opportunistic infection has occurred with biologic use is the onset of immune reconstitution inflammatory syndrome (IRIS) upon drug withdrawal. Although originally described in human immunodeficiency virus (HIV) patients receiving highly active antiretroviral therapy, it has become clear that IRIS may occur when recovery of immune function follows opportunistic infection in the setting of previous immune compromise/suppression. In this review, we draw attention to this potential pitfall on the use of biologic drugs.

Pleural effusion, pneumothorax, and lung entrapment in rheumatoid arthritis.

AbstractRheumatoid arthritis (RA)–associated pleural effusions are usually small and asymptomatic with no need for intervention, but complex and symptomatic rheumatoid pleural effusions may be seen and are associated with significant morbidity and mortality. Pleural effusions may develop before, concurrently with, or after the joint manifestations of RA. The classic features of RA-associated pleural effusions include high cell counts and protein, lipid, and lactate dehydrogenase levels and very low glucose levels, along with distinctive cytopathologic findings: slender spindle-shaped cells, multinucleated giant cells, eosinophilic granular debris, and the absence of mesothelial cells. Rarely, rheumatoid pleural involvement can include pneumothorax or can be severe enough to progress to lung entrapment, which may cause significant restrictive lung disease and require surgical therapy. Rheumatoid pleural involvement may not always correlate with joint activity but can be a significant cause of shortness of breath for patients with RA.

Utility of Immunologic Testing in Suspected Rheumatologic Disease

The use of diagnostic testing in the clinical practice of medicine has been a shifting landscape from the time that the first blood test was utilized. This is no different in the field of immunology and in particular rheumatology. As the field of immunology is relatively young, the clinical tests are not well established and therefore guidelines for use are still under debate. In this review, we seek to look at some of the key autoantibodies, as well as other tests that are available to diagnose suspected rheumatologic disease, and examine how to best use these tests in the clinic. In particular, we will focus on the anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, complement, cryoglobulins, rheumatoid factor, and anti-citrullinated protein antibodies.

Rituximab-responsive nephrotic syndrome due to minimal change disease in systemic lupus erythematosus.

CASE We present a 15-year-old African-American adolescent girl who presented with arthralgia, headache, facial rash, and pleuritic chest pain. Her examination was significant for synovitis in metacarpophalangeal and proximal interphalangeal joints, malar rash, and generalized pitting edema. Laboratory tests showed leukopenia (3.2 10 cells/L), elevated erythrocyte sedimentation rate (ESR; 60 mm/hr), low complement 4 (C4) level (10 mg/dL), low albumin (1.9 g/dL), elevated serum cholesterol, and normal creatinine (0.7 mg/dL). Urinalysis revealed significant proteinuria on dipstick with trace hemoglobin and no casts. The 24-hour urine collection showed 3.4 g of protein. Antinuclear antibodies (ANAs) were positive (1:640; speckled), with presence of anti-SSA and anti-SSB antibodies and elevated antiYdouble-stranded DNA antibodies. On the basis of her serology results and clinical presentation, she was diagnosed with systemic lupus erythematosus (SLE). On renal biopsy, pathologic examination showed absence of glomerular proliferation or necrosis with negative immunofluorescence studies. Epithelial foot process fusion and a thickened basement membrane were noted, compatible with minimal change disease (MCD). She was treated with prednisone 40 mg daily and furosemide with rapid resolution of symptoms. She was also started on hydroxychloroquine 200 mg twice daily, and prednisone was tapered to off for the next 2 months. For the next 5 years, her clinical course was complicated by several similar episodes of nephrotic syndrome, highly responsive to high-dose (60 mg daily) prednisone tapers with recurrence off prednisone. Other etiologies of MCD including medications such as anti-inflammatory medications and antibiotics were ruled out based on a detailed history. Additional immunosuppressive therapy was tried to prevent flares, including azathioprine and cyclophosphamide, which failed to prevent recurrences, and mycophenolate mofetil, which she could not tolerate. In November 2009, she developed an erythematous rash involving her face, arms and chest, along with anasarca. Laboratory tests revealed leukopenia (2.97 10 cells/L), elevated creatinine (4.67 mg/dL), low complement levels, and elevatedESR (72mm/hr). Serumalbuminwas 1.8g/dL.Urinalysis showed hematuria, proteinuria, nondysmorphic red cells, and granular casts. Spot urine protein-to-creatinine ratio was greater than 3.5. Skin biopsy revealed interface dermatitis. Renal ultrasound showed enlarged kidneys measuring 15 cm in size. A repeat kidney biopsy showed a moderate amount of epithelial foot process fusion, absence of glomerular crescents or necrosis, and negative immunofluorescence, again compatible with MCD (Figure). She responded quickly to prednisone and furosemide, with resolution of edema and return of creatinine to normal levels in 7 days. With recurrent episodes of nephrotic syndrome now leading to renal failure and inability to use other immunosuppressive medications, the decision was made to administer rituximab (2 doses of 1000 mg 2 weeks apart). Ten days after administration of the first dose, her rash had started fading. Within 4 weeks of administration of her second dose, her complement levels had normalized, ESR had decreased (44 mm/hr), and her proteinuria had resolved. Follow-up ultrasound revealed normal-sized kidneys. Prednisone was tapered off for the next 2 months, and she has been maintained on hydroxychloroquine. She has not had a recurrence since and continues to be symptom free at 24 months.

Three unusual mimics of primary angiitis of the central nervous system

To present three rare mimics of primary angiitis of the central nervous system (PACNS). We describe 3 patients with rare diseases that can mimic PACNS at clinical presentation and neuroimaging. We describe the clinical course of these patients and also present a review of the literature regarding these three diagnoses. All 3 patients presented with neurological symptoms and had abnormal findings on neuroimaging suggestive of PACNS. After detailed history, careful review of systems, thorough laboratory workup and consideration of lack of a response to immunosuppressive therapy, PACNS was ruled out with identification of an alternative diagnosis. PACNS is a rare disease and a diagnostic challenge with many differentials. A thorough investigation and awareness of unusual disorders is critical in avoiding misdiagnosis.

Diffuse alveolar hemorrhage and Libman-Sacks endocarditis as a manifestation of possible primary antiphospholipid syndrome.

AbstractAntiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of circulating autoantibodies against phospholipid-binding plasma proteins, leading to an increased risk of thrombosis and pregnancy loss. The most common manifestation of lung disease in APS is pulmonary embolism, which may often be the presenting symptom. We present a 30-year-old man with probable primary APS (with no history of thromboses) presenting with diffuse alveolar hemorrhage, an uncommon presentation. He was also found to have severe mitral valve regurgitation and during valve replacement surgery had cardiac vegetations compatible with a presentation of Libman-Sacks endocarditis. There are only 21 other reported cases of diffuse alveolar hemorrhage occurring as a result of APS. This is the first case of Libman-Sacks endocarditis in the setting of probable APS and alveolar hemorrhage.Diffuse alveolar hemorrhage should be considered as a nonthrombotic manifestation of APS, even in the absence of known thromboses, and may be the presenting symptom.

Remitting Seronegative Symmetrical Synovitis and Pitting Edema

Remitting seronegative symmetrical synovitis and pitting edema (RS3PE) is an uncommon condition that is characterized as an acute polysynovitis associated with pitting edema that tends to affect individuals who are over 50 years of age. This condition was first described by McCarty et al. in 1985 and although now usually thought of as a separate entity was originally thought to represent a subset of late onset rheumatoid arthritis (LORA). The controversy over the last 30 years as to whether RS3PE is a separate entity or forms a part of a clinical spectrum that includes LORA and polymyalgia rheumatica (PMR) is due to the similarities in clinical and demographic characteristics that are shared by these conditions. Additionally, RS3PE is also considered a paraneoplastic condition as it is often associated with malignancy. In this chapter, we will discuss the epidemiological and clinical characteristics of RS3PE, associated conditions including malignancy, diagnosis and management, as well as current data on mechanism of disease pathogenesis including areas of ongoing research and future directions.