Rapidly Progressive Glomerulonephritis

All types of small-vessel vasculitis and SLE can cause rapidly progressive glomerulonephritis (RPGN). This is potentially reversible, pathological process of fibrinoid necrosis and crescent formation, which, if left untreated, results in end-stage renal failure and death within days to weeks. Clinical features, blood test and the presence and pattern of renal immune deposition, helps distinguish the cause. The most common cause of RPGN is anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis (AASV), in which situation renal immune deposits are absents, creating a ‘pauci-immune’ appearance. Rarer primary causes of RPGN include anti-glomerular basement membrane (GBM) disease, Henoch-Schönlein purpura, and cryoglobulinaemic vasculitis. Unlike AASV, in all of these conditions RPGN is associated with immune deposits within the kidney. RPGN occurs in 80% at first presentation and is frequently asymptomatic, being identified by the presence of haematuria and proteinuria. 30% of RPGN present with ESRF requiring dialysis. Milder renal involvement with haematuria and proteinuria yet stable renal function may also occur, often identified when patients present with extra-renal disease. Due to its multi-system involvement, vasculitis can present in a variety of ways. Constitutional symptoms such as fatigue, weight loss and fevers are common. The non-specific symptomatology and lack of clinical suspicion can, unfortunately, result in diagnostic delay for several months, with major impact on long-term outcomes. Symptoms of other organ involvement tend to allow earlier diagnosis, e.g. pulmonary hemorrhage, peripheral neuropathy, skin rash, joint or ear, nose and throat disease. The absence of extrarenal symptoms usually results in a late diagnosis associated with worse renal function. When diagnosing vasculitis the following point are important to consider: (1) Infections, malignancy and vasculitis may present with similar constitutional symptoms, (2) RPGN and a positive ANCA can occur in infective endocarditis, (3) Granulomatous conditions, e.g. tuberculosis and sarcoidosis, may be confused with Wegener's granulomatosis, (4) Cavitating lung lessions and lung hemorrhage may be asymptomatic and a chest X-ray should be performed when vasculitis is suspected, (5) Blood tests for ANCA, eosinophil count, anti-GBM antibody, ANA, dsDNA, cryoglobulins, immunoglobulins, C3 and C4, help distinguish causes of RPGN, (6) Haematuria and proteinuria and red cell casts on urine microscopy represent glomerular bleeding and are highly suspicious for RPGN, (7) A renal biopsy with both light microscopy and immunofluorescence microscopy is the gold standard diagnostic test for RPGN, (8) Infections must be excluded before starting immunosuppressive therapy. Early treatment of RPGN is vital to reverse inflammation and renal failure, preventing irreversible kidney damage. Immunosuppresive therapies are used and treatment is classified as remission induction, remission maintenance, and relapse therapy. For 30 years the standard treatment for remission induction has been cyclophosphamide and corticosteroids. Current treatment regimens allow remission rates of 80-90%. However, a one-year mortality of 10% still exists, largely due to treatment toxicity. Cyclophosphamide is associated with high infection rates, an increased risk of ovarian failure in young women, and bladder cancer. Previously, oral cyclophosphamide was used for at least a year. Now on the basis of randomized controlled data, 3-6-month courses are used and some UK centres have switched to intravenous cyclophosphamide, associated with similar remission rates but reduced toxicity. Oral prednisolone is initiated at high doses (1 mg/kg/day) and reduced over 6 months to less than 10 mg/day. For patients with severe renal involvement (creatinine > 500 mjumol/litre) recent data suggest that the addition of plasma exchange improves renal recovery rates. The goal of remission induction therapy is to achieve an improvement and stabilization of renal function. Remission from RPGN is supported by the absence or reduction of blood and protein on urine dipstick testing and a negative ANCA. Relapses are common in AASV so prolonged immunosuppression is used. After remission induction, cyclophosphamide is replaced with a less potent immunosuppressant, usually azathioprine or methotrexate. Treatment is continued for approximately 2 years along with low-dose oral steroids, following which therapy may be withdrawn. ANCA-negative patients and those with microscopic polyangiitis are less likely to relapse compared to those with persistent ANCA positivity or Wegener's granulomatosis. Before therapy withdrawal the likelihood of relapse should be considered. 50% of patients with ANCA-associated vasculitis will relapse within five years. In the case of renal relapse, a repeat renal biopsy is useful to confirm the degree of disease activity. For relapse affecting major organs, such as the kidneys, re-introduction of high-dose steroids and cyclophosphamide are used with plasma exchange for severe renal disease. For minor relapse where major organs are not affected an increase in steroids may be sufficient. Ten percent of patients will either have frequent relapses or be intolerant of standard therapies. For these patients, alternative treatments include rituximab (anti-CD20 monoclonal antibody), intravenous immuniglobulin, mycophenolate mofetil and anti-TNF-alpha therapy. Renal prognosis and patient survival depends on the level of kidney failure at diagnosis. Good outcomes are usually obtained in those presenting with a creatinine less than 500 mjumol/l, with 90% surviving with independent renal function. Of those with advanced renal failure there is 25% mortality in one year, and 25-50% develop ESRF.

A flare is a measureable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.

Lupus 20 (2011): 453-462

Mycophenolate mofetil is an alternative to cyclophosphamide as first-line therapy for lupus nephritis.

Medicine 35 (2007): 516-520

Vitamin B Complex in Systemic Lupus Erythematosus

Immune therapy with folate in mice minimizes the symptoms of SLE and prolongs life span. The higher plasma levels of homocysteine might be associated with atherosclerosis in SLE, which reinforces the need for a higher consumption of vitamins B6 and B12 (in addition to folate), which are important cofactors in its metabolism and promote a reduction in homocysteine levels. In addition, those vitamins also influence the serum levels of some inflammatory markers, such as cytokines and C-reactive protein (CRP). Some studies have shown that the consumption of vitamin B12- and folate-deficient diets has caused a plasma increase in homocysteine in patients with SLE. Thus, it has been suggested that patients on a hypolipid diet (indicated for SLE) should increase their consumption of cereals fortified with those nutrients, in addition to vegetables and fruits. The possibility of supplementation should also be considered.

Systemic Lupus Erythematosus: Investigation

There is no necessity to order a whole host of serologic tests for every patient. These tests are best ordered with a clinical question in mind and interpreted accordingly. The anti-dsDNA Ab test should not be used as a screening test for SLE because it is present only about 60% of patients with lupus even when repeated over time. Neither is its presence alone diagnostic of SLE. Besides reflecting active SLE, it is linked to renal involvement. In clinical practice, the main value of the anti-dsDNA Ab is as an indicator of disease activity and in monitoring the patient's response to treatment especially in nephritis. There are exceptions to this. Some patients have been reported to have high levels this antibody without disease activity, and on the other hand, it may be negative during active disease, particularly when organs other than kidneys are affected. Prospective studies have also shown a rise in anti-dsDNA Ab levels well before a major SLE flare and a decrease at the time of or following a flare. A patient with high anti-dsDNA Ab should be observed more closely. The trend of the anti-dsDNA Ab levels in a patient is more relevant in clinical practice than its absolute value.

The Anti-Ro/SSA Ab is ordered when suspecting the rare ANA-negative lupus or when secondary Sjögren's syndrome is considered. More commonly, it is ordered together with anti-La/SSB Ab and the antiphospholipid antibodies (aPLs) (immunoglobulin G [IgG] and immunoglobulin M [IgM] anticardiolipin antibodies [ACA], lupus anticoagulant [LA], anti-B2 glycoprotein I [anti-B2GP I]) when a patient plans to start a family. Anti-Ro/SSA Ab and anti-La/SSB Ab are associated with neonatal lupus (NNL). The incidence of congenital heart block due to NNL in the offspring of a mother with anti-Ro Ab is about 2%, with a recurrence rate of 16% in subsequent pregnancies. Antiphospholipid antibodies (aPLs) are ordered when secondary APS is suspected and before pregnancy to assess the risks in pregnancy to fetus and mother and the need for closer monitoring and prophylactic treatment with aspirin.

Complete blood count and white blood cell differential are informative and inexpensive tests for assessing activity in clinical practice. A normochromic and normocytic anemia is consistent with any chronic illness or an acute blood loss such as in pulmonary hemorrhage (note: hemoptysis may be clinically absent during pulmonary hemorrhage). A macrocytic anemia suggests hemolysis, and the reticulocyte count is high in this instance unless there is a vitamin B12 or folate deficiency. Data from the LUMINA study have shown that anemia/hematocrit is a predictor of not only disease activity but also damage accrual. Leukopenia and lymphopenia indicate active SLE unless patient is already on immunosuppresive drugs such as cyclophosphamide when the possibility of adverse drug reactions has to be entertained. Azathioprine often increases the mean corpuscular volume but rarely causes a pancytopenia. Thrombocytopenia indicates either active SLE or associated secondary APS (when platelets are often only slightly rather than markedly reduced). In a pregnant patient with lupus, thrombocytopenia may be due to active disease or a variety of other causes including secondary APS; pre-eclampsia; and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome associated with pregnancy; heparin therapy; and the gestational state itself.

ESR and complements C3 and C4 are used in conjunction with anti-dsDNA Ab to assess disease activity. A high ESR indicates active disease, although at times, it may remain persistently high without any evidence of lupus activity. In this instance, look for evidence of secondary Sjögren's syndrome, occult infection, or malignancy. In the presence of a high ESR, C-reactive protein (CRP) may help differentiate active SLE from infection when it is normal or slightly elevated. CRP is moderately raised in patients with SLE with manifestations of serositis and Jaccoud's arthropathy, and therefore, in these instances, it is not useful in the exclusion of infection. Complements C3 and C4 are low in active lupus. Rarely, patients may have persistent hypocomplementia due to inherited complement deficiencies, such as the C4A/C4B null allele that is associated with lupus. During pregnancy, complement C3 and C4 may rise to supranormal levels, and a flare with complement activation may occur despite apparantly normal levels of complements C3 and C4. It is more helpful to follow the trend of the component levels to predict disease flare in pregnancy. Urine analysis for red and white blood cells, protein, and cellular casts are important tests of renal activity and may reveal clinically silent renal disease. During pregnancy, the patient with history of renal involvement may have a worsening of proteinuria due to physiologic response to pregnancy or pre-eclampsia and not necessarily a flare of lupus nephritis. In this instance, there should not be any feature of active urinary sediments. Blood urea, electrolyte, and serum creatinine should be ordered at baseline. A high creatinine with active urinary sediments indicates active lupus nephritis and warrants prompt initiation of treatment and further investigations such as renal ultrasound and biopsy to avoid delay in instituting appropriate immunosuppresants.

A chest x-ray study is routinely ordered before starting corticosteroids or immunosuppresants. In countries in which the infection is endemic and when individuals are at high risk for hepatitis B, screening gor this infection should be ordered because fulminant hepatitis may occur when high-dose corticosteroids or immunosuppresive drugs are used. All patients should have a baseline assessment of fasting lipids and glucose, calcium, phosphate, and bone mineral densitometry (when indicated). When appropriate, electrocardiograms, stress echocardiography, or other cardiac screening measures and duplex scanning of the carotids may be ordered.

Neuropsychiatric Lupus Syndromes: American College of Rheumatology Classification

The American College of Rheumatology has delineated 19 specific presentations of SLE affecting the nervous system. Twelve involve the CNS, of which five are behavioral (acute confusional state, mood disorder, anxiety disorder, psychosis, cognitive dysfunction), three are function related (movement disorder, myelopathy, demyelinating state), and four are classified as others (aseptic meningitis, cardiovascular state, headache, seizure disorders). Seven involve the peripheral nervous system, of which four are nerve related (mononeuropathy, cranial neuropathy, polyneuropathy, autonomic neuropathy) and three are classified as others (Guillain-Barre syndrome, myasthenia gravis, plexopathy). Just about any part of the brain can be affected by any of the lupus syndromes.

Hematologic Abnormalities in Systemic Lupus Erythematosus

Anemias are seen in 80% of patients with SLE. The most common causes include an anemia of chronic disease aggravated by factors associated with menstruating women such as heavy periods or iron deficiency. Other comorbidities such as vitamin B12 deficiency (seen in other autoimmune syndrome such as atrophic gastritis with antibodies to intrinsic factor), sickle cell anemia (since one in 250 black women have lupus), or thalassemia, or circulating factors inhibiting erythropoiesis should be considered as well. Ten percent of patients with lupus evolve end-stage renal disease, which is also associated with anemia. Nevertheless, consideration of a hemolytic anemia should always be contemplated as a cause of marked anemia, especially in young women, including children and adolescent. Patients with autoimmune hemolytic anemia (AIHA) can be readily identified because they have most of the following: an elevated serum lactate dehydrogenase (LDH), reticulocyte count, low haptoglobin, and positive direct Coombs’ test. Patients appear pale and tired. AIHA can be the presenting symptom of lupus. Attention is next focused on the platelet count. AIHA with autoimmune thrombocytopenia, or Evan’s syndrome, is found in a significant minority of this group. Combinations of anemia and thrombocytopenia should warrant consideration of microangiopathic hemolytic anemia as part of thrombotic thrombocytopenic purpura (TTP). This life-threatening combination consists of the pentad of hemolytic anemia, thrombocytopenia, renal impairment, CNS changes, and fever, and is often brought on by infection. Viewing a peripheral smear or bone marrow examination frequently helps make a definitive diagnosis, as well as obtaining ADAMTS13 levels (a von Willebrand factor protease). Also, approximately 15% of patients with lupus run low platelet counts as a manifestation of generalized inflammation. A subgroup of young women with SLE present with isolated idiopathic thrombocytopenic purpura (ITP) months to years before lupus develops. Leukopenia in SLE is almost always due to lymphopenia and result from antilymphocyte antibodies, medications such as corticosteroids (lymphocytosis with lymphopenia), or infection. It is rarely of clinical significance and only roughly correlates with inflammatory activity. Managing the cytopenias of SLE depends on the underlying cause. Repletion of vitamin B12, iron, hormonal interventions, and dietary supplementation may be helpful. Hemolytic anemias mandate high-dose corticosteroids (1 mg/kg/day) for 4 to 12 weeks, along with the institution of an immunosuppresive agents. Case reports and case series have suggested that mycophenolate mofetil, cyclophosphamide, azathioprine, and rituximab are efficacious. The agent if choice should depend on whether or not other manifestation (e.g., liver, renal, pulmonary) of SLE are present. Thrombocytopenias are rarely treated unless platelet counts drop below 60,000/mm3. As with anemias, the management of thrombocytopenias depends in part on the presence of extrahematologic disease. ITP quickly responds to moderate-dose corticosteroids, but refractory cases may benefit from the addition of azathioprine, cyclophosphamide, or rituximab. Life-threatening ITP with platelet counts below 10,000/mm3 are usually managed with intravenous immune globulin. About 70% of refractory cases respond to splenectomy.

Anti-Calcium Sensing Receptor Antibodies in Autoimmune Hypoparathyroidism

Autoimmunity is an important cause of hypoparathyroidism, either as an isolated endocrinopathy or as a component of autoimmune polyglandular syndrome (e.g., APS1 and 2). The parathyroid glands are infrequent target for autoimmunity; the exception being in the autoimmune polyglandular syndrome type 1, where autoimmune hypoparathyroidism is the rule. Antibodies that are directed against the parathyroid cell-surface calcium-sensing receptor (CaSR) have recently been recognosed to be present in the serum of patients with autoimmune hypoparathyroidism. In some individuals, these anti-CaSR antibodies have also bee shown to produce functional activation of the receptor, suggesting a direct pathogenic role in hypocalcemia. Additionally, a few hypercalcemic patients with autoimmmune hyperparathyroidism owing to anti-CaSR antibodies that inhibit receptor activation have now been identified. Other novel parathyroid autoantigens are starting to be elucidated. These findings suggest that new approaches to treatment, such as CaSR antagonist or agonist (calcilytics/calcimimetics) may be worthwhile.

Gout and Hyperuricemia in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology, characterized by chronic immune activation and multiple immunologic phenotypes, which predominantly affects women between the ages of 15 and 40. SLE can involve various organ systems, of which kidney involvement is a major concern, affectibg ~50% of patients and accounting for significant morbidity and mortality in western countries, and the 5-year survival in SLE patients with renal involvement is very low even with treatment. However, it has been reported that early diagnosis and prompt treatment may dramatically modify the course of renal disease and improve long-term survival. Therefore, early detection and diagnosis of lupus nephritis (LN) appear to be of great importance. Uric acid (UA) is a breakdown product of ingested and endogenously synthesized purines, which undergoes no further metabolism in humans and is excreted by the kidneys and the intestinal tract. Serum UA level is influenced by factors such as renal excretion function, states of high cell turnover, ingestion of food and drinks containing purines, etc. It is well known that UA crystals are the causative agents of gout. Recently, it has been demonstrated that UA is capable of activating the NLRP3 inflammasome, which plays important role in some inflammatory responses including gout. However, a number of epidemiologic studies have reported that high UA levels in serum are associated with a wide variety of disorders, such as cardiovascular disease (CVD), hypertension, diabetes, insulin resistance, metabolic syndrome, and so on. Furthermore, it has been found that although 29% of SLE patients were hyperuricemic, gout has rarely been reported in SLE patients. On the other hand, some cases of coincidental SLE and gour had been reported associated with nephropathy, but the detailed association between elevated serum UA level and the development of lupus nephritis in SLE patients without gout remained unclear.

Gout and Hyperuricemia

Gout is a condition characterized by the deposition of monosodium urate crystals in the joints or soft tissue. The four phases of gout include asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout and chronic tophaceous gout. The peak incidence occurs in patients 30 to 50 years old, and the condition is much common in men than in women. Patients with asymptomatic hyperuricemia do not require treatment, but efforts should be made to lower their urate levels by encouraging them to make changes in diet or lifestyle. Acute gout most commonly affects the first metatarsal joint of the foot, but other joints are also commonly involved. Definitive diagnosis requires joint aspiration with demonstration of birefringent crystals in the synovial fluid under a polarized light microscope. Treatment includes nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids and analgesics. In patients without complications, NSAID therapy is preferred.

Inhibition of Autoimmunity by Royal Jelly: A Hypothesise

Royal jelly (RJ) is the milky-white gelatinous substance secreted from the cephalic glands of nurse worker bees (Apis mellifera) for the sole purpose of stimulating the growth and development of the queen bee. Because of the presence of a variety of biologically active compounds, such as free amino acids, simple sugars, proteins, short chain hydroxy fatty acids, trace elements and vitamins, RJ is believed to be a functionally active supplement, not only for the bees but also for humans. RJ has been reported to possess several pharmacological activities including anti-allergic, anti-inflammatory and immunomodulatory properties. Thus, protective action of RJ against autoimmune diseases may be attributable to the effect of several ingredients of RJ on the immune system. The anti-inflammatory action of major RJ protein 3 ( MRJP3) through the inhibition of proinflammatory cytokines, such as TNF-alpha, IL-6 and IL-1 has been reported. Although several case reports demonstrating the role of RJ in the induction of asthma and anaphylaxis have been reported, reports providing experimental evidence on the effect of RJ in the suppression of allergic reaction through the restoration of macrophage function and Th1/Th2 cytokine responses have also been published. In addition, a recent report showed that purified RJ fatty acids, namely 10-hydroxy-2-decanoic acid (10-HAD) and 3,10-dihydroxy-decanoic acid (3,10-DDA) possessed immunomodulatory activies in vitro manifested generally by the DC-dependent inhibition of allogenic T-cell proliferation and IL-2 production, as well as the suppression of the antigen-specific immune response in vivo. Conversely, RJ has been reported to be associated with immunostimulatory functions through the induction of proinflammatory cytokine production. On the basis of the contents of the previously published reports and our findings in this study, we therefore hypothesise that the protection of mice against SLE by RJ, as manifested by a prolongation of lifespan associated with the amelioration of disease activities, may be a balancing action of different RJ ingredients favouring the host.

In human being, excessive protein intake causes a constant bone mineral loss in patients with juvenile SLE. On the other hand, the consumption of a protein-restricted diet (0.6 g/kg/day) has improved the glomerular filtration rate in the predialytic chronic kidney disease of patients with systemic diseases.

Rev Bras Reumatol 52 (2012): 384-408

Dyslipoproteinemia in Systemic Lupus Erythematosus: An Introduction

The autoimmunity and the inflammatory process of SLE are directly related to changes in lipid profile and to the metabolism of lipoprotein in SLE. The dyslipoproteinemia of the disease is characterized by higher levels of triglycerides (TG) and very-low-density lipoprotein cholesterol (VLDL-C) associated with lower levels of high-density lipoprotein cholesterol (HDL-C). Patients with both active and inactive disease show those lipid changes, which are aggrevated by the higher inflammatory activity of the disease, demonstrating that SLE by itself promotes a proatherogenic lipoprotein profile. A reduction in the enzymatic activity of lipoprotein lipase is responsible for determining a dyslipoproteinemia characteristic of the disease, because it reduces the catabolism of TG-rich lipoproteins (chylomicrons and VLDL-C) due to either the presence of anti-lipoprotein lipase antibodies (anti-LPL) or the action of the tumor necrosis factor-alpha (TNF-alpha). Several drugs used to treat SLE determine deleterious changes in the lipid profile previously altered by the disease itself, the effect of corticosteroids being of particular importance. Their chronic use in SLE is associated with an increase in total cholesterol and its fractions and TG, which can be observed after 1-2 months of treatment. It is already known that, for each 10-mg/day increase in the dose of prednisone, a 7.5-mg% elevation in total cholesterol is observed. In addition, corticosteroids induce the appearance of other risk factors, such as obesity, systemic arterial hypertension (SAH), hyperinsulinemia, and insulin resistance. Hyperinsulinemia increases oxidative stress, which is considered an important pathophysiological mechanism for the development of atherosclerosis. Some studies have evidenced that diabetes mellitus (DM) is significantly more common in patients with SLE than in the general population, because of the reduced insulin sensitivity, and that approximately 18-38% of the patients have metabolic syndrome (MS). It is worth nothing that more than half of the patients with SLE have three or more risk factors for cardiovascular disease, particularly obesity, SAH, and dyslipidemias, suggesting that they are really more susceptible to the MS. A Brazilian assessment of the nutritional status of 170 patients with SLE has reported a 1.2% prevalence of grade I thinness and a 64.2% prevalence of excessive weight (35.9% of overweight; 21.8% of grade I obesity; 4.1% of grade II obesity; 2.4% of grade III obesity). Eutrophy, according to the Body Mass Index (BMI), has been observed in only 34.7% of the patient assessed, leading to the conclusion that excessive weight is a frequent finding during the follow-up of patients with SLE. Thus, it is extremely important to establish strategies, such as programs to encourage the practice of physical activity and body weight reduction, in addition to nutritional counseling, to reduce the risk of MS. In addition, the hyperlipid diet (rich in cholesterol and saturated fat) is one of the major factors for maintaining dyslipidemia in SLE, perpetuating and aggravating lipid profile changes. On the other hand, antioxidant nutrients, such as beta-carotene, alpha-tocopherol, ascorbic acid, and selenium are known to protect against tissue damages by both activating macrophages, monocytes and granulocytes, and suppressing the activity of cytokines and TNF-alpha. Diet therapy is a promising way to approach SLE, with the indication of vitamin- and mineral-rich foods (mainly the antioxidant ones) and mono/polyunsaturated fatty acids, and moderate energy consumption, aiming at reducing inflammatory markers and helping in the treatment of those comorbidities and of the adverse reactions to drugs.

Evidence for the Role of Environmental Agents in the Initiation or Progession of Autoimmune Conditions: Ultraviolet Radiation and Ozone

Ozone is one of the most powerful oxidizing agents known and one of the most difficult air pollutants to control. The major source of ozone in the atmosphere is from the use of petroleum products, although it occurs naturally in the stratosphere and, ironically, forms a protective layer to our exposure to UV radiation. Both ozone and UV radiation have significant immunosuppresive activity. Exposure of experimental animals to ozone leads to decreased numbers of residents alveolar macrophages, probably through direct cell lysis. Their mobility and phagocytic activity are also decreased, as are intracellular antimicrobial enzymes such as lysozyme and acid phosphatase. Splenocytes lose responsiveness to antigens and T-cell mitogens, and both thymic and splenic atrophy are seen. In children, ozone decrease CD4-CD8 T-cell ratios. Ozone damage appears to be mediated through reactive intermediates such as hydroxyl radicals, singlet oxygen, and peroxides that may oxidize lipid membranes and thiols and alter methylation and protein-binding sites on DNA. On the basis of these observations, it is intriguing to consider a putative role of ozone in either the establishment or the progression of an autoimmune disease. However, at present, there are no substantial data that address this issue. UV light is also associated with the induction of systemic immunosuppression, and exposure of mice to UVB radiation (280-320 nm) results in the development of epidermal carcinoma. Indeed, UVB radiation is well established as a high risk factor in skin cancers in man. Reduction in delayed-type hypersensitivity response and bacterial resistance has also been shown for UVB exposure, although adaptation may occur with prolonged exposure. In vitro, UVB radiation inhibits mixed leukocyte reactions. Exposed allogeneic stimulators display decreased MHC class II expression and IL-2 release, whereas UVB-irradiated responders do not proliferative in response to allogeneic cell stimulators. Hence, immunosuppression appears to be caused by direct cellular damage and not induction of suppressor mechanism. There is no evidence as yet for the role of ozone or UVB radiation in the induction o autoimmune disease. Nonetheless, there are included as they may have potential effects, and ozone has already been shown to increase antigenicity of proteins, leading to increased IgE. Further work on UV irradiation is clearly required. At presents, the association with autoimmune disease is primarily speculative based on in vitro data and extrapolation of immune responses in mice.

Evidence for the Role of Environmental Agents in the Initiation or Progession of Autoimmune Conditions: Organic Solvents

Systemic sclerosis incorporated a broad spectrum of immune-mediated disease. Its major diagnostic criterion, abnormal thickening of the skin (scleroderma) proximal to metacarpophalangeal joints, belies both its severity and the frequent involvement of internal organs. Diffuse cutaneous and limited cutaneous forms of systemic sclerosis are widely accepted subdivisions of disease, and in both, antinuclear autoantibodies are common (~90%). An increased risk of systemic sclerosis appears to be associated with occupational exposure to organic solvents. A recent epidemiologic study confirmed solvent-disease associations with systemic sclerosis, particularly among patients positive for antibodies against the enzyme Scl-70 (a DNA topoisomerase I). One-quarter of all systemic sclerosis patients in the United States have antibodies Scl-70; these are marginally more prevalent in patients with the diffuse cutaneous form of disease (~35%) compared to those with limited cutaneous disease. This former showed a stronger association with organic solvent exposure than the latter. Although solvents may be categorized into different chemical groups such as aromatic hydrocarbons, aliphatic hydrocarbons, and chlorinated solvents, distinct association between disease and a single group is difficult. Solvents are often mixed, and their very nature as solvents means that the role of dissolved solutes cannot be excluded in disease. The mechanisms and genetics of susceptibility in VC disease may provide clues to the pathogenesis of organic solvent disease.

Evidence for Role of Environmental Agents in the Initiation and Progession of Autoimmune Conditions: Canavanine

Canavanine is an analogue of L-arginine produced by plants to reduce their palatability. Dietary canavanine, obtained through alfalfa, has been implicated in SLE-like syndromes and SLE has even been induced experimentally in macaques by feeding them alfalfa seeds. The monkeys developed autoimmune hemolytic anemia, antibodies to double-stranded DNA, immune complex-mediated glomerulonephritis, and arthritis. Autoantibodies continued for up to 2 years after discontinuation of alfalfa from the diet. In vitro, high doses of canavanine inhibit DNA synthesis in murine leukocytes; lower doses selectively inhibit B-cell function. In contrast to L-arginine, which has pI of 10.8, the pI for canavanine is 8.2. Following its ingestion and uptake, it may substitute for arginine in endogenous proteins, modifying their structure and function. Surface changes in the B cells of autoimmune mice were altered by dietary canavanine and other studies have shown that proliferative responses of human peripheral T cells, notably cytotoxic (CD8+) T cells, are inhibited by this nonessential amino acid. The combination of surface modification of B cells and inhibition of CD8+ cells could potentially lead to loss of tolerance. More directly, however, the substitution of arginine by canavanine, perhaps at the level of transfer RNA^arg in mammals, would render self-molecules immunogenic.

Cardiac involvement is one of the main complications substantially contributing to the morbidity and mortality of patients suffering from systemic autoimmune diseases. All the anatomical heart structures can be affected, and multiple pathogenic mechanisms have been reported. Non-organ-specific autoantibodies have been implicated in immune complex formation and deposition as the initial triggers for inflammatory processes responsible for Libman–Sacks verrucous endocarditis, myocarditis and pericarditis. Anti-phospholipid antibodies have been associated with thrombotic events in coronary arteries, heart valve involvement and intra-myocardial vasculopathy in the context of primary and secondary anti-phospholipid syndrome. Antibodies-SSA/Ro and anti-SSB/La antigens play a major pathogenic role in affecting the heart conduction tissue leading to the electrocardiographic abnormalities of the neonatal lupus syndrome and have been closely associated with endocardial fibroelastosis.