Lupus Natural Treatment

Natural Lupus Treatment System

Dr. Gary Levin is helping lupus patients with a step-by-step system that rehabilitates your immune system and boosts the bodys natural supporting systems to begin eliminating all lupus symptoms. The step-by-step treatment involves Directed Nutrition and a vitamin regime, helps the patient to lose weight, get rid of hair loss and it reduces the constant aches and pain, numbness and tiredness. Actually there is no cure yet discovered for lupus, however, you will find methods to control and manage its signs and symptoms. The aim of the treatments of lupus generally would be to let the patient experience more comfort and lesser pain. More here...

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Cellular and Cytokine Aberrations in Lupus Erythematosus

A great deal of literature is devoted to the description of the multiple and frequently contradictory immune cell abnormalities encountered in SLE, since aberrations of the immune cells are believed to play a major role in the pathogenesis of lupus. These studies have improved our understanding of the disease, helped us design novel treatments, and guided the search for the involved genes. Although the cellular aberrations in LE may reflect secondary effects, therapeutic modulation of the cellular abnormal Monocytes from patients with LE display a variety of abnormalities, including decreases in phagocytic activity, IL-1 production, expression of surface human leukocyte antigen (HLA)-DR, and accessory function for T-cell activation. In addition, LE monocytes fail to express the co-stimulatory B7 molecules after activation. These defects may partially explain the defective responses of lupus T cells to nominal antigens. In contrast, peripheral blood monocytes from patients with LE...

Membrane Mediated Signal Transduction in Lupus Immune Cells

Fresh circulating lupus T cells (whole T cells, CD4+ cells, and CD8+ cells) as well as lupus T-cell lines and autoantigen-specific lupus T-cell clones displayed significantly increased free intracellular Ca2+ responses compared with the responses of T lymphocytes, T-cell lines, or autoantigen-specific T-cell clones from healthy individuals or patients with systemic autoimmune diseases other than SLE. The mechanism for the increased intracellular Ca2+ responses is not known at this point, although involvement of linker for activation of T cells (LAT) and overactiva-tion of phospholipase C-gamma (PLC-y) have been suggested. The possibility of defective down-regulation of the Ca2+ response is attractive, and one candidate for such a role is the Ca2+-response down-regulator cyclic adenosine monophosphate-dependent protein kinase A type I. Activation of protein kinase A type I in T cells decreases the efflux of intracellularly stored free calcium. The Ca2+ pathway critically influences...

The Epidemiology of Lupus Erythematosus

Lupus erythematosus (LE) is an autoimmune disorder that includes a broad spectrum of clinical forms, ranging from those with lesions confined to the skin to others with more generalized involvement, then termed systemic LE (SLE). Although previously considered a rare disease, LE now seems to be relatively common in certain groups, probably owing to the development of several immunologic tests that identify many atypical or benign cases that otherwise might not be diagnosed. Furthermore, since the introduction in 1982 by the American College of Rheumatology (ACR) of a set of more sensitive criteria for SLE classification, more cases are now being detected. It is noteworthy that cutaneous manifestations account for 4 of the 11 revised criteria for the classification of SLE.

Incidence and Prevalence of Lupus Erythematosus Incidence

Incidence of systemic lupus erythematosus in several studies in Europe Table 3.1. Incidence of systemic lupus erythematosus in several studies in Europe Table 3.2. Incidence of systemic lupus erythematosus in several studies in the United States Table 3.2. Incidence of systemic lupus erythematosus in several studies in the United States

Epidemiology of the Cutaneous Manifestations of Lupus Erythematosus

CCLE includes classic localized discoid LE (DLE), generalized DLE, hypertrophic verrucous DLE, lupus panniculitis (lupus profundus), and chilblain LE. DLE is characterized by inflammatory plaques with scaling, follicular, plugging, atrophic scarring, central hypopigmentation, and peripheral hyperpigmentation. Approximately 5 of patients with isolated localized DLE subsequently develop SLE. It has been postulated that SLE is seven-fold more common than DLE. Chronic discoid lesions may be the initial manifestation of SLE in approximately 10 of patients, and they can occur during the course of the disease in 15 -30 of patients. It has been suggested that patients with SLE and discoid lesions may have a more benign clinical course, with less severe renal disease, than unselected patients with SLE (Callen 1985). In another study that included 136 patients with DLE (Le Bozec et al. 1994), the authors described the development of SLE in 11 of them. Interestingly, most of these patients...

Discoid Lupus Erythematosus

Carpet Tack Lupus

Classic discoid lupus erythematosus (DLE). Slightly infiltrated, erythematous plaques with scarring atrophy in a patient with thera-peutically refractory facial DLE Fig. 6.8. Perioral pitted scarring in discoid lupus erythematosus (DLE). Perioral DLE lesions often resolve with a striking acneiform pattern of pitted scarring Fig. 6.9. Discoid lupus erythematosus (DLE) of the scalp. Irreversible scarring alopecia as a result of persistent activity in localized areas Fig. 6.8. Perioral pitted scarring in discoid lupus erythematosus (DLE). Perioral DLE lesions often resolve with a striking acneiform pattern of pitted scarring Fig. 6.10. Total irreversible alopecia in discoid lupus erythematosus (DLE). In this patient, the disease process has progressed to the point of total irreversible scarring alopecia with secondary bacterial superinfection Fig. 6.11. Mucosal discoid lupus erythematosus (DLE). Typical appearance of a buccal lesion on the hard palate with a honeycomb...

Cutaneous Lupus Erythematosus in Children Introduction and Epidemiology

The incidence of LE in childhood has been estimated to be 0.6 in 100 000 per year (Lehman 1993). The incidence of CLE in childhood is probably lower. Girls outnumber boys among adolescents with LE, but the effect of sex is not so strong in younger children (Schaller 1982). The prevalence of lupus in black, Asian, and Hispanic children has been reported to be three times that in white children (Siegel and Lee 1973).

Acute Cutaneous Lupus Erythematosus

Transient Maculopapular Butterfly Rash

The typical clinical manifestations of ACLE are characterized by a localized erythema known as the malar rash or butterfly rash on the central portion of the face or by a generalized, more widespread form (Fabbri et al. 2003, Sontheimer and Provost 2003). Localized ACLE may only affect the skin transiently, and the lesions may last for only several days up to a few weeks. Therefore, at the onset of disease, the patients may mistake this rash for sunburn and may seek medical advice only after the lesions have persisted for a longer period. Generalized ACLE, also known as photosensitve lupus rash, is a less common variety and may be located anywhere on the body however, it has a predilection for sun-exposed areas of the face, extensor aspects of the arms and forearms, and the dorsal aspects of the hands. It generally presents as a maculopapular or exanthematous eruption with a pruritic component. In most of the patients, systemic manifestation is strongly associated with ACLE, preceding...

Subacute Cutaneous Lupus Erythematosus

Subacute Cutaneous Lupus

Papulosquamous subacute cutaneous lupus erythematosus (SCLE). Psoriasiform lesions with superficial scale and the tendency for individual lesions to merge into a vetiform pattern systemic disease, and only half of them have four or more of the American Rheumatism Association (ARA) criteria for the diagnosis of systemic lupus erythematosus (SLE) (Cohen and Crosby 1994, Crowson and Magro 2001, Tan et al. 1982). Therefore, SCLE can be considered a relatively benign illness that is intermediate in severity between ACLE and CCLE (Sontheimer 1989). Fig. 6.5. Annular subacute cutaneous lupus erythematosus (SCLE). Polycyclic lesions with central hypopigmentation and inflamed erythematous borders on the extensor aspects of the arm Fig. 6.6. Hypopigmentation in subacute cutaneous lupus erythematosus (SCLE). Permanent vitiligo-like depigmentation in the face of a patient with SCLE

Lupus Erythematosus Profundus

Lupus Profundus

LEP, historically referred to as Kaposi-Irgang disease or also known as lupus pan-niculitis, is a rare variant of CCLE in which pathologic changes occur primarily in the lower dermis and subcutaneous tissue. In 1883, subcutaneous nodules associated with LE were first described by Kaposi (Kaposi 1883), but the term lupus profundus was coined by Irgang (Irgang 1940) in 1940. Subsequently, different authors reported new cases and contributed to define the clinical and histopathologic characteristics of this disease (Arnold 1956, Sanchez et al. 1981, Tuffanelli 1971, Winkelmann 1970). Middle-aged women are predominantly affected however, in a recent study it has been shown that LEP in Asian patients is more frequent in a younger age group compared with the Caucasian population (Ng et al. 2002). The course of this subtype of CCLE is usually chronic and characterized by periods of remission and exacerbation. The major morbidity is usually disfigurement and disability related to pain, and...

Of Cutaneous Lupus Erythematosus

Handatlas Kaposi

The term lupus erythemateaux was used for the first time by Cazenave (Cazenave 1851) in 1851 to distinguish the noninfectious forms of lupus from cutaneous tuberculosis (lupus vulgaris). Cazenave referred in his original paper to Biett's earlier report on this disease, which was termed erytheme centrifuge, as being a very good description of what nowadays would be called discoid lupus erythematosus (DLE). Also, in 1845, Hebra (Hebra 1845) precisely described systemic manifestations of LE that occurred in patients who had the classic butterfly erythema, which he named seborrhea congestive. Since the earlier descriptions had always discussed LE in the context of cutaneous tuberculosis, it is very much Cazenave's achievement to have clearly separated LE from an infectious disease, thus clearing the way for further studies on this complex disease following other hypotheses and directions. The most extensive description on the systemic manifestations of LE at that time must be referred to...

Prognosis of Cutaneous Lupus Erythematosus

Systemic lupus erythematosus (SLE) is one of the most frequently seen autoimmune disorders. Prevalence rates vary between 14 and 50 per 100,000 population (Hochberg 1997). Cutaneous LE (CLE) presumably occurs two to three times more frequently than SLE. However, exact population-based epidemiologic data are not available. In selected groups of patients with LE cared for in dermatology departments, the prevalence of patients with chronic discoid LE (DLE) varies between 42 and 72 (Kind and Goerz 1987, Tebbe and Orfanos 1987), and subacute cutaneous LE (SCLE) is found in 7 -32 of the entire collective (Molad 1987, Sontheimer et al. 1979, Tebbe and Orfanos 1987). Table 14.1. Prognostic factors of cutaneous lupus erythematosus (LE) discoid LE and subacute cutaneous LE

Lupuslike Syndromes Related to Drugs and Environmental Factors

Autoimmunity develops in relation to many environmental agents, including drugs, chemical agents, dietary factors, and infectious agents (Mongey and Hess 1996). Until now, more than 70 drugs have been related to the onset of drug-related lupus. In general, skin manifestation is not frequently observed in patients with drug-related lupus, although there are no specific diagnostic criteria. Approximately 25 of patients with hydralazine-induced lupus develop skin manifestations. In contrast, skin lesions in procainamide-induced lupus are said to absent. Some anticancer agents are well known to induce photosensitivity and lupus-like lesions (Ghate JV et al. 2001, Yoshimasu et al. 2001b). Among anticancer agents, a mixture of uracil and tegafur is common in Japan. The review of 17 Japanese cases of discoid LE-like lesions induced by fluorouracil agents enabled us to establish the mouse model (Yoshimasu et al. 2001a, 2004), which provides new insights for better understanding the discoid...

The Relationship of Cutaneous Lupus Erythematosus Lesions and UV Light Implications for Pathogenesis

The description of the markedly photosensitive subset of subacute cutaneous LE further clarified this relationship between UV irradiation and lesion development (Sontheimer 1989). UV irradiation of skin is associated with the generation of increased numbers of apoptotic keratinocytes (sunburn cells), and UV irradiation of kera-tinocytes in vitro induces apoptotic death (Casiola-Rosen et al. 1994, Young 1987). It is therefore of particular interest that the pathology of cutaneous lupus is predominantly a lichenoid reaction in which apoptotic keratinocytes are enriched (Chung et al. 1998, Pablos et al. 1999). The association of photosensitivity with a unique autoantibody response to Ro and La in both adult and neonatal forms of LE has suggested that skin lesions result from an interplay between UV-induced skin changes and preexistent, specific immune effector pathways. Significant evidence in support of such a model has accumulated in recent years.

The Specific Autoantibody Response as a Probe of Disease Mechanisms in Systemic Lupus Erythematosus

There is a growing consensus that the highly specific humoral immune response to autoantigens in systemic autoimmune diseases is T-cell dependent and that flares of disease result when this primed immune system is rechallenged with self-antigen (Diamond et al. 1992, Radic and Weigert 1994). The molecules targeted in SLE are ubiquitously expressed in most nucleated cells but seem to share nothing in common in terms of structure, function, or subcellular distribution in control cells (Casciola-Rosen et al. 1995, Rosen and Casciola-Rosen 1999). The mechanisms responsible for initiation and propagation of the immune response to this highly specific group of autoantigens remain unclear (Bach and Koutouzov 1997). Several years ago, we postulated that although these autoantigens have no apparent unifying characteristics, they likely satisfied the stringent criteria for initiation of a primary immune response at the onset of disease (e.g., presentation in a proimmune context of suprathreshold...

The Role of T Cells and Adhesion Molecules 19 in Cutaneous Lupus Erythematosus

Immune response to skin antigens modified by ultraviolet (UV) radiation is currently proposed as the pathomechanism for skin lesions in lupus erythematosus (LE) (Cas-ciola-Rosen and Rosen 1997, Norris 1993,1995, Norris et al. 1997). Cellular apoptosis brought about by UV radiation is believed to have an important role in inducing and perpetuating the disease, but the in vivo role for apoptosis in cutaneous LE (CLE) remains unclear (Orteu et al. 2001). A multistep model has been proposed in which the first step is the release of soluble proinflammatory epidermal and dermal mediators, which may be genetically regulated. A particular allele of interleukin (IL) 1 has been associated with systemic LE (SLE) severity and photosensitivity (Blakemore et al. 1994), and a high tumor necrosis factor (TNF)-a response is linked to the HLA-DR3 gene (Wilson and Duff 1995,Wilson et al. 1993). The HLA-DR3 gene is reported to associate with the most photosensitive variant of CLE, subacute CLE (SCLE)...

CAMs in Cutaneous Lupus Erythematosus

Figurate Erythema Dermatology

Examples of expression patterns of cellular adhesion molecules (CAMs) in UV-induced skin lesions in patients with cutaneous lupus erythematosus (CLE). Cryostat sections, mouse monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular adhesion molecule-1 (VCAM-1) (Vectastain Elite ABC)

Specific Laboratory Tests that Can Be Abnormal in Cutaneous Lupus Erythematosus

Laboratory Differences Between the various subtypes of cutaneous lupus erythematosus (CLE). Modified from Sontheimer and Provost 1997 Table 23.2. Laboratory Differences Between the various subtypes of cutaneous lupus erythematosus (CLE). Modified from Sontheimer and Provost 1997

Laboratory Testing and Progress to Dissemination of Systemic Lupus Erythematosus

Approximately 15 of patients with CLE eventually progress to SLE (Rowell 1984). Several studies have been undertaken to determine the clinical and laboratory features that may predict such a pattern of disease progression. Clinically, patients with generalized DLE are at higher risk of developing SLE, oftentimes with more severe manifestations (Callen 1982). Laboratory tests associated with the development of SLE in patients with DLE include severe leukopenia, unexplained anemia, false-positive serologic tests for syphilis, persistently positive, high-titer ANA, anti-single-stranded DNA antibody, hypergammaglobulinemia, an elevated ESR greater than 50 mm h, and a positive lupus band test (Callen 1982). A study in 1997 showed that in SCLE and or DLE, patients with evidence of nephropathy, arthralgias, or ANA titer of 1 320 were at significantly higher risk of having systemic disease (Tebbe et al. 1997). This study did not find ESR and anti-ds-DNA antibodies to be useful in...

ANAs in Cutaneous Lupus Erythematosus

SLE is a multisystem disorder with symptoms spanning from relatively benign cutaneous eruption to a severe, in some cases fatal, systemic disease. Although SLE can affect virtually every organ, abnormalities of the skin or mucous membranes are very frequent, being the second most common manifestation of SLE. Cutaneous lesions occur in approximately 85 of patients with SLE and are associated with photosen-sitivity, which may be linked to the pathogenesis of the underlying autoimmune response. The idea is that ultraviolet (UV) irradiation of the skin may expose previously cryptic antigens on the cell surface of epidermal cells, which, in turn, may be recognized by autoantibodies and T cells as foreign components, leading to (a) a systemic autoimmune response and (b) production of lupus skin lesions. Fig. 24.1. Subcellular distribution of Ro SSA. A Indirect immunofluorescence and confocal microscopy of HEp-2 cells with subacute cutaneous lupus erythematosus (SCLE) autoanti-bodies against...

Systemic Lupus Erythematosus

Arteriolar Hyalinization

Involvement of the CNS occurs in 14-75 of patients with systemic lupus erythematosus (SLE) 4 . Pathologically, microinfarcts and small vessel vasculopathy are the most common. Vasculopathy affects predominantly the arterioles and capillaries, resulting in vessel tortuosity, vascular hyalinization, endothelial proliferation and perivascular inflammation or gliosis. Systemic lupus erythematosus in a 39-year-old woman with recurrent episodes of stroke, who presented with fever and disturbance of consciousness. a T2-weighted image shows hyperintense lesions in the right thalamus, internal capsule, putamen, subcortical white matter, and the left internal capsule (arrows). b Gadolinium-enhanced T1-weighted image reveals marked enhancement of the lesion in the right side,suggesting blood-brain barrier breakdown (arrows). c DW image shows a slightly hyperintense lesion in the right thalamus but an isointense lesion in the right putamen and white matter (arrows). There is a linear hyperintense...

Differential Diagnosis at Particular Sites Discoid Lupus Erythematosus of the Scalp

Scutula Favus

A Atrophic alopecia in discoid lupus erythematosus. Note the widened erythematous follicular openings between flattened atrophic areas. B Lichen ruber planopilaris confluent small areas of atrophic skin with interspersed unaffected hair-bearing follicles Fig. 11.2. A Atrophic alopecia in discoid lupus erythematosus. Note the widened erythematous follicular openings between flattened atrophic areas. B Lichen ruber planopilaris confluent small areas of atrophic skin with interspersed unaffected hair-bearing follicles

UV Irradiation Induces Apoptosis of Keratinocytes and Clustering of Lupus Autoantigens in Apoptotic Surface Blebs

Because the epidermis is one of the physiologic targets of the immunopathologic response in lupus, several groups have established an in vitro epidermal model to address the fate of autoantigens in keratinocytes after irradiation with UVB (Casci-ola-Rosen et al. 1994, Furukawa et al. 1990,Golan et al. 1992,LeFeber et al. 1984,Natali and Tan 1973). One of the striking observations made was that several lupus autoantigens (including Ro SSA, La SSB, snRNP, and Sm) that are normally intracellular could be stained extracellularly in monolayers of human keratinocytes incubated for 20-24 hours after UV irradiation (Furukawa et al. 1990, Golan et al. 1992, LeFeber et al. 1984). Using a similar in vitro system, we demonstrated that keratinocytes become apoptotic within a few hours of irradiation (Casciola-Rosen et al. 1994). Further studies showed that the lupus autoantigens are strikingly redistributed in apoptotic cells, and they become clustered into two populations of structure at the...

Nonspecific Skin Lesions in Patients with Systemic Lupus Erythematosus

Vascular lesions play a dominant role. Raynaud's phenomenon occurs frequently in SLE, as it does in other collagen vascular diseases. Leukocytoclastic vasculitis may arise, often associated with periods of increased disease activity it may present as cutaneous necrotizing vasculitis (palpable purpura) or as urticarial vasculitis, less often as arteritis, with symptoms similar to polyarteritis nodosa. Thrombophlebitis and thrombotic vessel damage is seen particularly in patients with secondary antiphospholipid syndrome, leading to livedo reticularis or acral cyanosis or necrosis. Thrombocytopenia may cause thrombocytopenic purpura. Similar to patients with dermatomyositis, patients with SLE often show nailfold erythema, telangiectasia, or hemorrhage. Characteristic nonspecific signs are thin, brittle hair with an uncombed appearance, referred to as woolly or lupus hair, and telogen effluvium.

Photosensitivity in Lupus Erythematosus12

Photosensitivity is a characteristic feature of all forms and subsets of lupus erythematosus (LE) that has been recognized since the first phenomenologic descriptions of this complex disease. In 1881, Cazenave (Cazenave 1881) described exacerbations of the disease related to cold, heat, fire, and direct action of the air, and Hutchinson (Hutchinson 1888) reported in 1888 that patients with LE did not tolerate the sun well. At the beginning of the 19th century, several physicians had already realized that environmental factors, such as sun exposure, play a role in the induction of LE (Pusey 1915, Macleod 1924, Freund 1929). Pusey (Pusey 1915) described in 1915 a young lady who had her first outbreak of cutaneous LE (CLE) a few days after extensive golfing in the summertime. The lesions disappeared after strict avoidance of the sun, but another exacerbation occurred during the next summer, again after a golf tournament. In 1929, Freund (Freund 1929) could clearly demonstrate in a large...

Identification of lupus loci in humans and mice

Linkage analysis of human multiplex kindreds carried out over the last 20 years has identified numerous lupus-susceptibility loci (Moser et al 1998, Gaffney et al 1998, 2000, Shai et al 1999, Johanneson et al 1999, Cantor et al 2004). Eight cytogenetic locations have been confirmed independently to be in linkage with lupus 1q23, 1q25-31, 1q41-42, 2q35-37, 4p15.2-16, 6p11-21, 12p24 and 16q12 (Tsao 2004). As with other complex diseases, cloning disease-associated alleles once linkage regions have been defined has been relatively unsuccessful. However, there is convincing evidence for lupus-associated alleles in three of the linkage regions CRP, FCGR2A, FCGR2B and FCGR3A at 1q23 (Zuniga et al 2001, Kyogoku et al 2002, Manger et al 2002, Lee et al 2002, Magnusson et al 2004), PARP1 at 1q41-42 (although studies of different PARP1 alleles have yielded contradictory results) (Tsao et al 1999, Criswell et al 2000), PDCD1 at 2q37 (Prokunina et al 2002) and the HLA-DR2 C4Q0 haplotype and TNFat...

Using ENU to discover lupus genes

By virtue of its high rate of random mutagenesis, and the overwhelming predominance of point mutations (Russell et al 1979, Vinuesa & Goodnow 2004), ENU is an excellent tool for investigating the allelic spectrum of disease. We have screened G3 mice from ENU-treated founders for the presence of ANA and commenced secondary analysis of mice for additional features of the lupus phenotype. So far, we have identified one strain, sanroque, in which a single coding SNP in the Rc3h1 (Roquin) gene causes an unequivocal lupus phenotype with ANA, dsDNA antibodies, autoimmune cytopenia, lymphadenopathy and glo-merulonephritis in 100 of homozygous pure B6 mice (Vinuesa et al 2005). Human RC3H1 is located in 1q25, within one of the 8 linkage regions that have been confirmed, and no candidate gene has been identified in this region so far. It only lies 10 Mb downstream from another linked region, 1q23, for which only SLE susceptibility genes with weak effects have been identified. Thus, Rc3h1...

In Cutaneous Lupus Erythematosus

In lupus erythematosus (LE), the skin organ is involved to a varying extent with gross intraindividual and interindividual differences. These differences have been referred to in detail in other chapters of this book. Dermatologic symptoms usually do not influence the survival of patients, but they do affect their quality of life and self-esteem to a great extent. In addition, cutaneous LE (CLE) mainly affects young and middle-aged patients and presents with a chronic course. Consequently, therapy has to be balanced for short- and long-term side effects and often may be restricted to safe yet effective local measures, including sun protection. Beyond these measures, antimalarials are the first-line treatment for cutaneous disease (Callen 2002, Duna and Cash 1995, Jessop et al. 2001, McCauliffe 2001, Patel and Werth 2002, Reid 2000, Werth 2001). However, physicians are often faced with the challenge of recalcitrant skin disease unresponsive to such conventional therapy and have to...

Old burntout Lesions of Discoid Lupus Erythematosus

A Actinic keratoses irregular, firm, hyperkeratotic masses (limestonelike) on erythematous ground. Note the photodamaged skin at the periphery. B M. Bowen a flat, irregularly hyperkera-totic, partially erosive lesion with polycyclic borders and little inflammation. C Discoid lupus erythematosus lesions of intermediate age with central atrophy and raised ery-thematous borders Lupus vulgaris in advanced stages may show similarity with scarring lesions of DLE. Whereas fresh lesions of lupus vulgaris are characterized by reddish brown macules and patches of soft and friable consistency that display a typical apple-jelly color on diascopy, more advanced lesions may exhibit considerable atrophy and scarring. As a distinguishing mark, remnants of tuberculous granulation tissue are often found at the periphery and in the centers if probed, the instrument tends to break through the overlying skin. Moreover, lupus vulgaris has a tendency to ulcerate, which is very uncommon in DLE,...

Subsets of Systemic Lupus Erythematosus

In the wide spectrum of clinical manifestations, different subsets of systemic lupus and clusters can be defined by clinical or serologic items. Relevant and established Table 13.3. Typical autoantibodies in patients with systemic lupus erythematosus (SLE) Table 13.3. Typical autoantibodies in patients with systemic lupus erythematosus (SLE) High titer in syndromes with features of polymyositis, lupus, scleroderma, and mixed connective tissue disease if present in SLE without anti-DNA, risk of nephritis is low Former antinuclear antibody- negative lupus, SLE, SCLE, Sjogren's syndrome, Sjogren lupus overlap, neonatal lupus, congenital heart block can be associated with nephritis (+ double-stranded DNA antibodies) Lupus anticoagulant, anticar-diolipin, and false-positive test result for syphilis the two former (particularly high-titer IgG) are associated with thrombembolic complications (such as strokes) and fetal losses correlation with disease activity and in high titers of high avid...

Psoriasis and Lupus Erythematosus

The coincidence of LE and psoriasis seems to be rare. Based on their prevalence in the population, the coexistence of psoriasis with all forms of lupus seems to be less than expected. Dubois (Dubois 1974) reported that 0.6 of 520 patients with systemic LE (SLE) had concurrent psoriasis. Tumarkin et al. (Tumarkin et al. 1971) described 637 patients with discoid LE (DLE), and only 1 had coexistent psoriasis. In 1927, O'Leary (O'Leary 1927) described one of the first cases of coexistent psoriasis and LE. Throughout the years, several explanations concerning this coexistence have been developed. Schaumann (Schaumann 1928) postulated that the combination of LE and psoriasis - disorders with different affinity to the ground on which they appear - must be sought in the etiologic factors determining their pathogenesis. Louste et al. (Louste et al. 1939) focused on the endocrine deficiency. Charpy et al. (Charpy et al. 1952) proposed that both disorders (in combination with arteriitis and...

Chilblain Lupus Erythematosus

Telangiectoid variant of discoid lupus erythematosus (DLE). Multiple erythematous plaques and reticulate telangiectasia on the face that produce large areas of disfigurement on confluence Fig. 6.15. Chilblain lupus erythematosus (CHLE). Red-purple patches on the finger end joints that are precipitated by cold, damp climates Because CHLE lesions are highly reminiscent of simple chilblains or pernio lesions (Viguier et al. 2001), one could question whether such patients have simple pernio that in the predisposed individual produces a Koebner's phenomenon resulting in DLE. The terms chilblain lupus and perniotic lupus have been used to describe such lesions. Unfortunately, the term lupus pernio has also been used for such lesions, although this term is more properly used to designate a form of cutaneous sarcoidosis (James 1992). For a positive diagnosis of CHLE, it has been proposed to establish two groups of major and minor criteria (Su et al. 1994). Major criteria include...

Apoptosis in Lupus Erythematosus17

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown etiology characterized by chronic, inflammatory damage of numerous tissues. The highly specific clinical phenotypes of SLE, the unique pathology, and the very specific autoantibody response associated with these phenotypes have provided critical insights into the pathogenesis of lupus. In this regard, photosensitive lupus skin disease and neonatal lupus have been particularly instructive, providing both common and unique insights into disease mechanisms (Buyon 1996, Orteu et al. 2001, Sontheimer 1989). For example, the skin is a prominent target tissue in both pheno-types, and there is a characteristic exacerbation of cutaneous disease after exposure to sunlight or to artificial sources of ultraviolet (UV) radiation (Buyon 1996, Orteu et al. 2001, Simmons-O'Brian et al. 1995, Sontheimer 1989). Similarly, both phenotypes are associated with the production of autoantibodies to highly specific targets, for...

Apoptosis Genes and Photosensitivity in Lupus

Apoptosis is a form of programmed cell death, over 6-48 h, that is characterized by cell shrinkage and nuclear condensation in response to the activation of the enzyme caspase 3 (Elkon 1997, Salmon and Gordon 1999). On early apoptotic keratinocytes, Casciola-Rosen (1997) reported the formation of surface blebs, which are highly enriched with several lupus autoantigens, including Ro SSA in genetically susceptible individuals, expression of this autoantigen is proposed to initiate an autoantibody response. Multiple stimuli, including UVR, cytokines, cytotoxic T cells, and cytotoxic drugs, are capable of inducing apoptosis (Arnold et al. 1999, Danno and Horio 1982, Elkon 1997, Haake and Polakowska 1993, Stone et al. 1998). The Fas transmembrane glycoprotein receptor (Fas, encoded by TNFRSF6) has an intracellular death domain that initiates a cascade of events when Fas binds external Fas ligand, leading to death of the cell by apoptosis. In normal human skin, Fas is found mainly in the...

Experimental Models of Lupus Erythematosus

The etiology and pathogenesis of autoimmune diseases cannot be readily analyzed without appropriate animal models, although no single animal model perfectly mimics a human disease. Animal models are commonly used to study the genetic, environmental, and pathogenic aspects of autoimmune diseases. Regarding experimental autoimmune diseases, these models can be divided into several broad groups (a) inbred mice that spontaneously develop a disease similar to human systemic lupus erythematosus (SLE) (b) chronic graft-vs-host diseases induced in F1 hybrid mice injected with lymphoid parental cells (c) ultraviolet (UV) light-irradiated mice immunized with some components of DNA (d) immunodeficient mice such as severe combined immunodeficient (SCID) mice and nude mice inoculated or engrafted with immunocompetent cells or tissues and (e) gene-manipulated mice such as trans-genic or knockout mice. There are many inbred strains of SLE-prone mice, including New Zealand Black (NZB), F1 hybrids of...

And Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisystem inflammatory autoimmune disease characterized by highly varied clinical manifestations in association with autoantibody production (antinuclear antibodies ANAs , anti-double-stranded DNA ds-DNA antibodies, and anti-extractable nuclear antigen antibodies). Next to, for instance, kidneys, brain, heart, and joints, the skin is one of the organs typically affected in lupus. Cutaneous manifestations of lupus erythematosus (LE) appear frequently at the beginning or in the course of SLE, but they may also occur without systemic involvement. This book deals with a broad spectrum of cutaneous forms of lupus with respect to the clinic, pathophysiology, and treatment. The aim of this chapter is to analyze what the skin is telling us about the autoimmune process below the surface. Several analyses tried to predict the clinical situation of the patients by their antibody profile or their genetic background,but as every patient with lupus is...

Clinical Photosensitivity in Lupus Erythematosus

Photoprovocation of subacute cutaneous lupus erythematosus (SCLE) with UVA (left test field) and UVB (right test field). Picture taken 10 days after the last irradiation. Characteristic genuine annular SCLE lesions on the shoulder of the patient. Fig. 12.1. Photoprovocation of subacute cutaneous lupus erythematosus (SCLE) with UVA (left test field) and UVB (right test field). Picture taken 10 days after the last irradiation. Characteristic genuine annular SCLE lesions on the shoulder of the patient. Table 12.1. Provocative phototesting in patients with lupus erythematosus (LE) optimized protocol (modified from Kuhn et al. 2001a) Table 12.1. Provocative phototesting in patients with lupus erythematosus (LE) optimized protocol (modified from Kuhn et al. 2001a) Table 12.1. Provocative phototesting in patients with lupus erythematosus (LE) optimized protocol (modified from Kuhn et al. 2001a) (continued)

Characteristics of Drug Induced Lupus Erythematosus

Systemic lupus erythematosus, often abbreviated SLE, is a serious autoimmune syndrome that usually affects young women. Most lupus is idiopathic, which means that its cause is unknown, but approximately 10 is associated with the use of specific drugs (Adams and Hess 1991). The diagnosis of drug-induced lupus is made on the same basis as idiopathic lupus in addition, the symptoms must have begun after initiation of treatment with a drug and must resolve on discontinuation of that drug treatment. Although the signs and symptoms of drug-induced lupus overlap with those of idiopathic lupus and the two syndromes cannot be differentiated on the basis of differences in signs and symptoms, the usual clinical picture is somewhat different. A significant difference is that drug-induced lupus is usually milder, and the most serious manifestations of idiopathic lupus are usually absent in the drug-induced variety. Despite the overlap in symptoms between idiopathic and drug-induced lupus, the...

Lupus Erythematosus

Keratoconjunctivitis Sicca Lupus

INTRODUCTION Lupus erythematosus is a chronic inflammatory autoimmune disease with a spectrum of clinical forms ranging from a benign chronic cutaneous variety (discoid lupus erythematosus) to an often-fatal systemic type with nephritis (systemic lupus erythematosus). Intermediate types, variously known as disseminated discoid lupus erythematosus and subacute cutaneous lupus erythematosus, are characterized by various combinations of widespread cutaneous lesions and mild to severe systemic manifestations. The role of immune complexes in the inflammatory manifestations of lupus is well recognized, and in about 4 of cases an associated vasculitis may be seen from small vessel involvement. Lupus erythematosus occurs most commonly in women in the third to fifth decades. When skin lesions occur they typically appear in areas exposed to the ultraviolet rays of the sun. Rarely discoid lupus can degenerate into squamous cell carcinoma. Common nonscarring eyelid lesions include a pruritic...

Autoantibodies and Immune Complexes

IgM antibodies to DNA are frequently produced in the normal host and bind to single-stranded (ss)DNA they have low affinity for DNA and broad cross-reactivity with a variety of other self-antigens. The production of these natural anti-DNA antibodies is tightly regulated, and they usually do not undergo isotype switching and are encoded by germline genes affinity maturation by the process of somatic mutation does not occur. On the contrary, anti-DNA antibodies in the serum of patients with SLE have quite different features in that they have undergone isotype switching to IgG of various subclasses, and germline genes usually do not encode them because new amino acids are introduced into their variable regions to enhance affinity (somatic mutations and hypermutations). Continuous receptor editing in lupus B cells may provide an additional impetus toward production of more pathogenic autoantibodies. Because DNA is a highly anionic macromolecule, positively charged amino acids,...

Environmental Factors

Various environmental factors, such as UV light, heavy metals, organic solvents, and infections, influence a genetically susceptible host in triggering the expression of SLE. Exposure to UV light causes photosensitivity (more frequently in the white LE population) and is a known disease-exacerbating factor. UV light causes apoptotic cell death of keratinocytes and cell surface expression of autoantigens previously hiddenin the cytoplasm or nucleus. Autoantigens presented on surface membrane blebs of discrete size become accessible for immune recognition and attack. The latter may result in local inflammation and the appearance in the circulation of autoantibodies. UV light irradiation of cultured human keratinocytes induced changes consistent with apopto-sis, and the autoantigens were clustered in two kinds of blebs of the cell surface membrane, the smaller blebs containing endoplasmic reticulum, ribosomes, and the (auto)antigen Ro SSA and the larger blebs containing nucleosomal DNA,...

Introduction and Epidemiology

Neonates are not sufficiently immunologically competent to develop IgG autoanti-body-mediated disease independently. However, IgG autoantibodies from the mother transmitted in utero can initiate disease in susceptible individuals. In a small percentage of fetuses and neonates exposed to maternal autoantibodies of the Ro SSA family, an autoimmune disease called neonatal lupus erythematosus (NLE) will develop (Lee 1993,2001). It may be argued that NLE is misnamed, as many of its clinical findings are not shared by systemic LE (SLE) of children or adults, but the name NLE remains in common use. The main features of the syndrome are cutaneous lupus lesions, cardiac disease (primarily complete congenital heart block), hepatobiliary disease, and hematologic cytopenias. Many affected individuals have only one manifestation of NLE, but any combination of these findings may occur.

Laboratory Evaluation

Skin biopsy is not always performed owing to the age of the child and the predilection of lesions for the face. Biopsy findings for histologic examination and immunofluorescence are consistent with the findings of SCLE (David-Bajar et al. 1992). Notably, there is basal cell damage and a lymphocytic inflammatory infiltrate in the upper dermis. Histologic features more closely associated with discoid lupus, such as an intense deep dermal inflammatory infiltrate, an intense periadnexal infiltrate, fol-licular plugging, and basement membrane thickening, are not prominent in NLE. In the author's experience, the immunofluorescent finding characteristic of cutaneous NLE is epidermal particulate deposition of IgG. This finding can be reproduced in an animal model by infusion of anti-Ro SSA antibodies (Lee et al. 1986,1989).

Sulfonamides and Sulfasalazine

The first report of drug-induced lupus involved a sulfonamide (Hoffman 1945), and yet the incidence of sulfonamide-induced lupus is very low. Sulfasalazine is associated with induction of a lupus-like syndrome, probably because it is metabolized to a sul-fonamide and another aromatic amine. Consistent with this hypothesis is the observation that the slow acetylator genotype is a very strong risk factor for sulfasalazine-induced lupus (Laversuch et al. 1995, Gunnarsson et al. 1997). Such an association is usually related to metabolism of aromatic amines, but the parent drug is not an aromatic amine. Renal disease seems to be common in sulfasalazine-induced lupus (Gunnarsson et al. 1997).

Involvement of Reactive Metabolites

The mechanism of drug-induced lupus is unknown however, there is a large amount of circumstantial evidence to suggest that the mechanism involves a chemically reactive metabolite. In the case of procainamide, sulfonamides and sulfasalazine, acebu-tolol, and practolol, the reactive metabolite is formed by oxidation of the aromatic amine functional group (Uetrecht 1988). Acebutolol and practolol are the only two blockers that are metabolized to aromatic amines, and they are also the only two for which there are good data to support a causal relationship with a lupus-like syndrome (Wilson et al. 1978). In a similar vein, minocycline is the only tetracycline that is an aromatic amine, and it seems to be the only tetracycline that is associated with a significant incidence of a lupus-like syndrome. In the case of minocycline, the reactive metabolite seems to be a quinone imine rather than a hydroxylamine, but its formation still involves oxidation of the aromatic amine. Hydralazine and...

Modification of Macromolecules

Modification of protein by a reactive metabolite (hapten) could lead to an immune response against the modified protein, including a response to the hapten. Antidrug antibodies have been reported in drug-induced lupus (Hahn et al. 1972) however, such antibodies are not a universal feature and are probably not pathogenic. Modification of a protein can also change the manner in which the protein is processed by antigen-presenting cells, and this can lead to the presentation of peptides that the immune system has not seen before and, therefore, have not been tolerized to. Such peptides are referred to as cryptic antigens. It has been suggested that an immune response against cryptic antigens could lead to an autoimmune response (Griem et al. 1998). Drug-induced lupus has many of the characteristics of a graft-vs-host reaction (Gleichmann et al. 1984). Reactive metabolites presumably modify many different proteins, and there is no reason to believe that they would not also modify major...

Inhibition of DNA Methylation

Procainamide and hydralazine were found to inhibit DNA methylation (Cornacchia et al. 1988). DNA methylation inhibits gene transcription, and so inhibition of DNA methylation could lead to lymphocyte activation. This is an attractive mechanism for the induction of lupus, and it does not require the formation of a reactive metabolite. However, it is conceivable that it is a reactive metabolite that is responsible for inhibition of DNA methylation. Decreased DNA methylation has also been reported in idiopathic lupus (Richardson et al. 1990). In unpublished studies, we found other drugs that inhibited DNA methylation to the same extent as procainamide, and yet the drugs involved are not associated with drug-induced lupus. Even if inhibition of DNA methylation is not the exclusive mechanism of drug-induced lupus, it may make a significant contribution to the mechanism for some drugs.

Inhibition of Apoptosis

The first pathogenic mechanism of lupus that was discovered in an animal model was a defect in apoptosis that prevented the deletion of autoreactive T cells (Watanabe-Fukunaga et al. 1992). One article reported that chlorpromazine increased apoptosis in lymphoblasts (Hieronymus et al. 2000) however, the effects were studied in vitro, and it is unclear whether the effects seen in this system are representative of the effects that occur in vivo. Procainamide and hydralazine had no effect on apoptosis, but it is unlikely that significant amounts of reactive metabolite would be produced in this system. To my knowledge, no work has been done in vivo to determine the effects on apoptosis of drugs associated with the induction of lupus.

Inhibition of Complement

It is known that patients with genetic deficiencies in the complement system, especially C2 and C4, have a high incidence of lupus and other autoimmune diseases, presumably because this leads to defects in the clearance of immune complexes (Dubois and Wallace 1987). Hydralazine and several other drugs interact with C4 and inhibit binding of C4 to C2, and it was proposed that this could represent the mechanism of drug-induced lupus (Sim and Law 1985). The hydroxylamine of procainamide also binds to C4 (Sim et al. 1988), but the concentration of this metabolite in vivo is unlikely to be sufficient to have much of an effect.

Significance of Photosensitivity

However, it seems likely that a personal history of polymorphous light eruption (PLE) is of predictive value for the development of CLE. Murphy and Hawk (Murphy and Hawk 1991) first suggested a possible relationship between PLE and LE in 1991, when they reported that 10 of their series of 142 patients with PLE had raised titers of ANAs or anti-Ro SSA antibodies. PLE and lupus symptoms consistent with PLE were reported in 50 -61 of patients with DLE and in 33 -55 of patients with SCLE. In most cases, PLE preceded the development of CLE by several years (Millard et al. 2001, Nyberg et al. 1997). A significantly higher PLE prevalence was found in relatives of patients with LE than in the general population (Millard et al. 2001).

Autoimmune Diseases in Hybrid Mouse

Several F1 hybrid mice have been used for the investigation of autoimmunity. The (NZWxBXSB)F1 mouse, which develops lupus nephritis with myocardial infarctions, is a model of idiopathic thrombocytopenic purpura (Oyaizuet al. 1988), and also shows serologic features resembling human antiphospholipid syndrome (Monestier et al. 1996). The (NZBxBXSB)F1 mouse is also a model of lupus nephritis (Merino et al. 1994). These studies gave new insights and a better understanding into the role of the Yaa gene in lupus development (Table 16.2). Although several other hybrid strains, including the (SWRxSJL)F1 mouse, in which both parental strains show lymphadenopathy, splenomegaly, and hyper-y-globulinemia (Vidal et al. 1994), have been proposed as models of SLE, there is little information available on lupus dermatoses.

Abnormal Clearance of Apoptotic Cells Renders Individuals Susceptible to Initiation of Systemic Autoimmunity

Epidermis develop inflammatory skin disease and features of SLE such as antinuclear antibodies and lupus nephritis resembling the human condition (Seery et al. 1997). Although the mechanisms involved have not been well defined, the authors suggest that apoptotic keratinocytes provide the source of self-antigens, which are likely processed by professional antigen-presenting cells that migrate from the epidermis to the dermis (likely attracted by IFN-y) and the draining lymph nodes.

Erythematosus The Role of Ultraviolet Light

Cutaneous lupus erythematosus (CLE) defines a spectrum of diseases, including subacute CLE (SCLE), LE tumidus (LET), discoid LE (DLE), and systemic LE (SLE). Of these, the most photosensitive are SCLE and LET. The anti-Ro SSA antibody and the human leukocyte antigen (HLA) DR3 genotype are strongly correlated with SCLE but are rarely present in DLE (Lee and Farris 1999) or LET (Alexiades-Armenakas et al. 2003).

UVR Light Causes Exposure of Autoantigens to the Immune System

Studies demonstrate a clonal expansion of T cells from CLE blood and skin, suggesting that lesions may be secondary to antibody-dependent cellular cytotoxicity (ADCC) (Furukawa et al. 1996, Kita et al. 1998). In vitro and in vivo studies show that antibodies from the serum of patients with LE bind to the surface of UVB-irradiated keratinocytes (Furukawa et al. 1990, LeFeber et al. 1984) and that this binding, along with UVB cytotoxicity, increases when using keratinocytes from patients with LE, DLE, or SCLE compared with controls (Furukawa et al. 1999). This increased binding is likely responsible for ADCC to keratinocytes (Furukawa et al. 1994, 1999). Other studies demonstrate that IgG1 anti-Ro SSA autoantibody can activate complement and ADCC (Bennion et al. 1990). Interestingly, estradiol augments the binding of anti-Ro SSA and anti-La SSB antibodies to irradiated keratinocytes, suggesting a link between increased prevalence of SCLE and LE in females (Furukawa et al. 1988)....

UVR Is an Important Immunomodulator

Third, UVB modifies the production of the chemokines CXCL1 and CXCL2 (Kondo et al. 2000), whereas UVA inhibits chemokine CCL17 production from keratinocytes (Zheng et al. 2003). CXCR3-activating chemokines (CXCL9, CXCL10, and CXCL11), as well as HLA-DR3 and ICAM-1, are preferentially expressed at the dermal-epidermal junction and periadnexal areas in DLE lesional skin. CD4+ and CD8+ dermal T cells are located in the same areas that express the CXCR3 receptor, suggesting that these chemokines may have an effect on leukocyte recruitment. Interferon (IFN)-y induces keratinocyte and macrophage expression of chemokines, HLA-DR3, and ICAM-1, suggesting that IFN-y has an important immunomodulatory role in DLE (Flier et al. 2001). Low levels of IFN-y are associated with a reduced autoantibody response in murine lupus models (Pollard 2002).

Dendritic Cells and Photosensitive Autoimmune Disease

Immature DCs are responsible for maintenance of peripheral tolerance to self-antigens, whereas mature DCs are responsible for the induction of immunity. IFN-y causes maturation of immature DCs into efficient APCs, and IFN-y can then act in an autocrine manner to activate DCs (Montoya et al. 2002). In patients with SLE, increased levels of IFN-y lead to DC activation and maybe responsible for a break in tolerance to self-antigens and an activation of the immune system (Pascual et al. 2003). Interestingly, IFN-y serum levels closely mirror disease activity in patients with lupus, and gene signatures of peripheral bone marrow cells from patients with SLE match those of IFN-y-regulated genes (Pascual et al. 2003). Further evidence that IFN-y drives DC differentiation in SLE is generated by the fact that antibodies to IFN-Y block the ability of SLE serum to induce differentiation of immature DCs, and addition of IFN-y to normal serum reproduces DC maturation (Blanco et al. 2001).

Humoral Autoimmune Responses Against Nuclear Proteins

Patients with systemic rheumatic diseases such as systemic lupus erythematosus (SLE), scleroderma, and Sjogren's syndrome characteristically produce antinuclear antibodies (ANAs) that recognize intracellular nucleoprotein complexes. Systemic rheumatic diseases constitute chronic, life-threatening, multiorgan autoimmune disorders (Reichlin 1998). Their etiology is unknown, but genetic, hormonal, and environmental factors are involved. SLE is best characterized as a systemic immune complex vasculitis due to continued production of autoantibodies directed against nucleoplasmic antigens (e.g., DNA, histones, spliceosomal components, ribonucleo-proteins), whereas scleroderma-associated autoantibodies primarily detect nucleo-lus-associated proteins such as DNA topoisomerase I (Scl-70) and centromeres. Autoantibodies target evolutionary, conserved epitopes of nucleoprotein complexes, which often constitute the functional regions (Tan 1989). Thus, the immunofluores-cence staining patterns...

Phenotypic heterogeneity

One possible explanation for the failure to identify susceptibility genes in complex disease is phenotypic heterogeneity. This is of particular concern in SLE, where the clinical manifestations are remarkably protean. Indeed, for the purposes of clinical and genetic studies, the lupus definition depends on fulfilling any 4 of 11 diagnostic criteria (Tan et al 1982, Hochberg 1997). Clearly, two individuals may meet the criteria for diagnosis while exhibiting completely independent phenotypes.

Indications and Dosage

Fig. 27.4. a 29-year-old patient with subacute cutaneous lupus erythematosus before therapy. b Complete clearing of skin lesions with extensive depigmentation two weeks after therapy with acitretin Fig. 27.4. a 29-year-old patient with subacute cutaneous lupus erythematosus before therapy. b Complete clearing of skin lesions with extensive depigmentation two weeks after therapy with acitretin

Thalidomide Analogues

Thalidomide analogues have been synthesized with the aim of developing drugs with better clinical efficacy and improved side effect profiles. These include thalidomide-template-based TNF-a inhibitors, which may be 50,000 times more effective in TNF-a inhibition. Two classes are described, according to inhibition of phosphodiesterase 4. Those without phosphodiesterase 4-inhibitory activity also co-stimulate T cells, although more potently than thalidomide (Corral and Kaplan 1999). However, there have been no reports to date of their clinical use in lupus, although they have been used in therapy of myeloma (M. Kazmi, personal communication). As the exact mechanisms for the efficacy of thalidomide in lupus are not known, it is difficult to know which properties would be important to retain in the analogue.

During Tolerizing Apoptosis

Apoptosis Lupus

Although many autoantigens targeted in SLE are redistributed in cells dying by apop-tosis, only ribonucleoprotein complexes containing La SSB, Ro SSA, Sm, and U1-70 kDa have been implicated in the pathogenesis of experimental photo-induced epidermal damage. It has been proposed that a pathologic immune response develops in patients with lupus against one or more of the photoproducts found in normal skin after UV irradiation, raising the possibility that these ribonucleoprotein complexes themselves (unlike other autoantigens) might be lupus chromophores. It is also possible that photoproducts that present in normal skin after UV irradiation might be metabolized abnormally in patients with lupus owing to genetic polymorphisms, predisposing to an exaggerated autoimmune response against these photo-products. The resulting immune response is directed against the UVB-induced complexes and subsequently spreads to individual component molecules (RNA and protein), generating an autoamplifying...

Dehydroepiandrosterone

The androgen dehydroepiandrosterone (DHEA) belongs to the group of steroid hormones that are produced by the adrenal cortex. In vitro, T lymphocytes, on exposure with DHEA, have been shown to produce increased amounts of Th1 cytokines such as IFN-y and IL-2, whereas the production of Th2 cytokines such as IL-4 was decreased (Daynes et al. 1990). Moreover, DHEA and DHEA-sulphate serum levels were found to be decreased in patients with SLE unrelated to disease activity or treatment (Jungers et al. 1982). In an animal model of lupus (female NZB NZW mice), treatment with androgens resulted in an improvement in disease activity. The ability of androgens to promote an immunodeviation toward Th1 as well as their efficacy in lupus mice prompted studies in humans (Melez et al. 1980). Accordingly, patients with lupus nephritis or severe cytopenias were treated with DHEA, 200 mg d. As a result of this treatment, no difference in SLE disease indices compared with placebo was noted. Only the loss...

Stem Cell Transplantation

Autologous stem cell transplantation recently has been introduced for the treatment of autoimmune diseases. Accordingly, in nine patients with life-threatening SLE who failed to respond to intravenous cyclophosphamide therapy, autologous hematopoi-etic stem cell transplantation in combination with high-dose chemotherapy (intravenous cyclophosphamide, 50 mg kg) has been performed. One patient died of disseminated mucormycosis, and one patient developed cytomegalovirus viremia before transplantation. The remaining seven patients showed an improvement and remained free of active lupus during 25 months of follow-up (Traynor et al. 2000).

Other Experimental Therapies

Bindarit is a propioic acid inhibitor that modulates cytokine and chemokine production in animal models of inflammation (Zoja et al. 1998). In an open-label pilot study using bindarit in 10 patients with lupus nephritis, a decrease in proteinuria was observed (Vigano et al. 1995). However, a follow-up placebo-controlled trial was never initiated.

Plasmapheresis and Immunoadsorption

Impaired clearance of immune complexes and the production of autoantibodies are characteristic features of LE. Therefore, it was conceivable that the extracorporal removal of these proteins may help improve LE lesions or support current treatments. Plasmapheresis is a procedure that separates plasma proteins from whole blood by cell centrifugation techniques or membrane technology. Subsequently, the plasma is replaced by albumin and saline. Usually plasmapheresis is combined with an immunosuppressive therapy to prevent antibody rebound or rapid resynthesis of immunoglobulins. This modality was first considered for therapy of lupus patients with hyperviscosity, cryoglobulinemia, pulmonary hemorrhage, or thrombotic thrombocytopenic purpura (Wallace 2001a). It also has been used successfully in the management of acute central nervous system involvement of lupus when other therapies have failed (Neuwelt et al. 1995). However, in a large international prospective controlled trial in...

Typical Laboratory Findings

As in idiopathic lupus, antinuclear antibodies (ANAs) are almost always present, and the pattern is usually homogenous. Although antibodies against single-stranded DNA are common, unlike idiopathic lupus, antibodies against double-stranded DNA are uncommon. Antihistone antibodies are classic (Fritzler and Tan 1978) however, they are not diagnostic because they are often present in idiopathic lupus, and the exact specificity is even different for lupus caused by different drugs (Burlingame and Rubin 1991, Portanova et al. 1987). Antineutrophil cytoplasmic antibodies, many with specificity for myeloperoxidase, are common (Dunphy et al. 2000, Nassberger et al. 1990). These antibodies may activate neutrophils and increase inflammation (Falk et al. 1990). Mild anemia, leukopenia, and thrombocytopenia are common. Complement levels are usually normal,but they can be depressed (Rich 1996). When the offending drug is discontinued, manifestations such as anemia usually resolve with other...

Maculopapular Exanthemas

Generalized exanthemas of SLE may appear as transitory indistinct morbilliform macular rashes that regress after hours or days and may wax and wane parallel to disease activity they may persist, however, and transform into more stable macular lesions that are well demarcated, are slightly hypertrophic and scaly, and somewhat resemble the lesions of SCLE. Some may acquire annular shapes or a tylotic morphology (e. g., chilblain lupus). All exanthemas of SLE, except the morbilliform rashes, are situated in the light-exposed areas (face,V region of the neck, extensor surfaces of the arms, wrists, and dorsa of the fingers). Following regression, they leave no atrophy or depigmentation (rather, hyperpigmentation in dark skin). Macular eruptions are clinically much less characteristic than the stable lesions. Acral vasculitic skin lesions in SLE present as flat, erythematous palmoplantar painful plaques or nodules and resemble chilblains (chilblain lupus). These lesions are also typically...

Genetic analysis of systemic autoimmunity

Even for complex diseases with high rates of monozygotic twin concordance, disease-associated alleles remain elusive. One explanation is that multiple common genetic variants with weak effects cause these diseases and identification of any single allele requires large cohorts. Conversely, if the allelic spectrum of complex disease is heterogeneous, strong effects of rare variants might be offset by their presence in only a small proportion of the patient population. Lupus (SLE) is a systemic autoimmune disease, with significant monozygotic twin concordance, protean clinical manifestations, and production of high-affinity pathogenic autoantibodies. This complex phenotype and results from genome scans point to multiple molecular defects. Contrary to this expectation, our analysis of ENU-mutagenized mice indicates that homozygous mutations frequently cause anti-nuclear antibodies (ANAs), and can account for a full blown lupus phenotype. The best characterized example is the...

Erythematosus

Thomas Ruzicka (Eds.) Cutaneous Lupus Erythematosus Cutaneous Lupus Erythematosus Cutaneous lupus erythematosus edited by Annegret Kuhn, Percy Lehmann, Thomas Ruzicka. p. cm. Includes bibliographical references and index. ISBN 3-540-44266-9 (alk. paper) 1. Lupus erythematosus. I. Kuhn, Annegret, 1967- II. Lehmann, Percy, 1953- III. Ruzicka, Thomas. DNLM 1. Lupus Erythematosus, Cutaneous-patholgoy. 2. Lupus Erythematosus, Cutaneous-therapy. WR 152 C988 2004

Abbreviations

ACLE acute cutaneous lupus erythematosus BLE bullous lupus erythematosus CCLE chronic cutaneous lupus erythematosus CHLE chilblain lupus erythematosus CLE cutaneous lupus erythematosus DLE discoid lupus erythematosus ICLE intermittent cutaneous lupus erythematosus LBT lupus band test LE lupus erythematosus LEP lupus erythematosus profundus LET lupus erythematosus tumidus NLE neonatal lupus erythematosus SCID severe combined immunodeficient SCLE subacute cutaneous lupus erythematosus SLAM Systemic Lupus Activity Measure SLE systemic lupus erythematosus SLEDAI Systemic Lupus Erythematosus Disease Activity Index snRNP small nuclear ribonucleoprotein

Genes and Genetics

The risk for development of LE in a sibling in families with a member with LE is 20 times more than in the general population. The relatively high concordance rates for SLE in monozygotic twins (25 -57 ) compared with dizygotic twins (2 -9 ) supports the importance of the genetic background. It is currently believed that multiple genes confer susceptibility to SLE expression, several of which have been identified to associate with lupus. Most of these associations have been identified while investigating pathogenic mechanisms in the disease. For example, the conjecture that certain MHC antigens should present autoantigens better than others led to unveiling of associations between the disease or individual manifestations and MHC antigens. On the other hand, the expectation that apoptosis-related genes should be associated with the expression of lupus was not fulfilled. More recently, genome-wide searches in families with multiple affected members disclosed areas in the genome...

Hormones

Although lupus affects prepubertal males and females equally, during puberty it manifests a striking preference for females that is maintained throughout the reproductive years. Thus, female hormonal factors play a permissive role at least, whereas male hormonal factors play a protective one in the expression of SLE. This has been further supported by studies in murine strains in which it has been clearly shown that estrogens have deleterious effects on lupus-prone experimental animals, whereas androgens are protective.

Conclusions

Summary of the major cellular aberrations involved in the pathogenesis of lupus erythematosus (LE). Multiple genetic, environmental, and hormonal factors instigate a variety of cellular and cytokine abnormalities. These abnormalities lead to increased production of autoanti-bodies, which either directly or after forming complexes with autoantigens and activating complement deposit in tissues and initiate an inflammatory response. Immune complexes are formed in excessive amounts in patients with LE and are cleared at decreased rates because the numbers or the function of Fc and complement receptors are decreased.APC, antigen-presenting cells autoAb, autoantibody CR, complement receptor FcR, Fc receptor IFN, interferon IL, inter-leukin MHC, major histocompatibility complex RES, reticuloendothelial system UV, ultraviolet Fig. 1.1. Summary of the major cellular aberrations involved in the pathogenesis of lupus erythematosus (LE). Multiple genetic, environmental, and hormonal...

Photoimmunology2

Among the wide-ranging environmental factors affecting human life, ultraviolet (UV) irradiation can be regarded as one of the most significant. Although UV light has an essential impact on terrestrial and aquatic ecology and is a fundamental necessity for the life of humans, animals, and plants, mid-wavelength UVB (290-320 nm) in particular can also exert hazardous effects on health. UV radiation not only plays an instrumental role in the development of skin cancer but also has profound effects on local and systemic inflammatory responses. While studying the biological effects of UVB irradiation, it has become evident that UV exposure can significantly compromise the immune system. The implications of the immunosuppres-sive properties of UV irradiation are manifold because UVB-induced immunosup-pression not only is responsible for the inhibition of protective cell-mediated immunity but also contributes to the initiation, development, and perpetuation of several skin disorders (Fisher...

Mortality Studies

Survival of patients with LE has increased significantly in the past 40 years. Studies performed in 1955 (Merrell and Shuldman 1955) showed a survival rate lower than 50 at 5 years, whereas recent studies (Abu-Shakra et al. 1995a, Gripenberg and Helve 1991, Pistinier et al. 1991, Seleznick and Fries 1991) indicate that approximately 93 of patients with LE survive more than 5 years, and 85 survive more than 10 years. In the Euro-Lupus project (Cervera et al. 2003), 92 survival was found after 10 years from the time of entry into the study, The improved survival of patients with LE has been associated with an alteration in the patterns of mortality. In 1976, Urowitz et al. (Urowitz et al. 1976) described a bimodal pattern of mortality, emphasizing inflammatory activity as the principal cause of death in patients with a recent diagnosis of SLE, whereas cardiovascular events were the most important cause of death in those with long evolution. Recently, epidemiologic studies observed that...

Photobiology

Of the different external factors that have detrimental effects on disease activity, the sun's radiation has been best studied. Already in Cazenave's original description (Cazenave 1881) it was mentioned that outdoor workers were predisposed to the disorder and that exacerbations of the disease were related to environmental factors. Hutchinson (Hutchinson 1888) reported in his Harveian Lectures on Lupus, published in 1888, that patients with LE did not tolerate exposure to the sun. In 1915, Pusey (Pusey 1915) described a young lady with LE that first appeared after some days of extensive golfing in the summertime. The lesions disappeared after strict avoidance of the sun, only to reexacerbate the next summer after a golf tournament. Freund (Freund 1929) evaluated in a study from 1920 to 1927 the admission of patients with LE to the Department of Dermatology in Berlin. He demonstrated an increased prevalence of new LE cases in May and June and concluded that climatic factors were...

Photosensitivity

Photosensitivity is commonly detected in patients with SLE. The frequency of photosensitivity varies with the geographical region and the specific lupus cohort studied. For example, our group reported a 45 frequency of photosensitivity in 150 patients with SLE evaluated in the Mid-Atlantic states in the United States (Hochberg et al. 1985). The late James Gilliam living in Dallas, Texas, believed that almost all of his patients with SLE were photosensitive (personal communication). Other studies have indicated that patients with subacute cutaneous LE (SCLE) possessing anti-Ro SSA antibodies have an 80 -90 frequency of photosensitivity (Mond et al. 1989, Simmons-O'Brien et al. 1995). Indeed, many of these patients burn through window glass, indicating that low-energy long-wave ultraviolet (UV) light is capable of activating their disease. Provocative phototesting has indicated that various subsets of lupus erythematosus (LE) have different frequencies of photosensitivity (Kuhn et al....

Alopecia

Three types of alopecia can be detected in patients with LE (Sontheimer and Provost 1996). In addition to the permanent scarring alopecia associated with discoid lupus lesions, patients with SLE may experience transient alopecia with increased disease activity. Two types of transient hair loss, a result of the severe catabolic effect of the Table 7.4. Comparative histologic findings in chilblain lupus erythematosus (LE) vs idiopathic chilblains (see Cribier et al. 2001,Viguier et al. 2001) Table 7.4. Comparative histologic findings in chilblain lupus erythematosus (LE) vs idiopathic chilblains (see Cribier et al. 2001,Viguier et al. 2001) lupus disease flare, have been detected. One is classic telogen effluvium, in which the patient develops prominent and at times alarming loss of hair all over the scalp. If the patient's SLE is a chronic active disease process, the telogen effluvium may persist for a prolonged time. However, with quiescence of the lupus disease process, normal growth...

Risk Factors

The incidence of idiopathic lupus is approximately 10-fold higher in females than in males. Although the incidence of drug-induced lupus is often said to be the same in males and females, as with many idiosyncratic drug reactions, it seems that the incidence is somewhat higher in females than in males. However, the issue is complicated by the fact that many categories of drugs are used more frequently by one sex than the other. For example, in Table 9.1,41 of patients with procainamide-induced and 64 of patients with hydralazine-induced lupus were females, but many more males than females are treated with these drugs. In one study, the incidence in males treated with hydralazine was 2.8 and that in females was 11.6 (Cameron and Ramsay 1984). Unlike idiopathic lupus, drug-induced lupus usually occurs in an older age group, and it has been reported to be more common in caucasians, whereas idio-pathic lupus is more common in blacks (Dubois and Wallace 1987). Specific HLA types have been...

Procainamide

Procainamide is associated with the highest incidence of lupus of any available drug. The incidence varies by study. This is probably because the incidence increases with time over a period of years. The average time to onset for slow acetylators is 12 months, but that for rapid acetylators is 48 months (Woosley et al. 1978). The incidence with prolonged therapy is close to 30 (Henningsen et al. 1975). The incidence of ANA development is even higher more than 90 with chronic therapy (Woosley et al. 1978). However, most patients with procainamide-induced ANAs are asymptomatic, so there is no rationale for monitoring ANAs in asymptomatic patients. Pleurisy and pulmonary infiltrates seem to be somewhat more common in pro-cainamide-induced lupus than in lupus associated with other drugs. Patients who develop procainamide-induced lupus can be treated with N-acetylprocainamide, a major metabolite of procainamide, although a small amount of this drug is converted back to procainamide (Stec...

Hydralazine

Hydralazine is also associated with a high incidence of drug-induced lupus. With chronic therapy, the incidence of ANA induction is approximately 50 and that of a symptomatic lupus-like syndrome is approximately 10 however, it depends on the acetylator phenotype (Perry 1973, Perry et al. 1970). In addition, as mentioned previously, the incidence is dose dependent, and if the daily dose is kept below 200 mg, the incidence is lower. Unlike most drug-induced lupus, there have been several reports of significant kidney involvement with hydralazine-induced lupus (Shapiro et al. 1984). As with procainamide, the use of hydralazine has significantly declined because many effective alternative drugs have been developed.

Isoniazid

One of the few other drugs that contain a hydrazine group is isoniazid. The incidence of circulating ANAs in patients treated with isoniazid is approximately 20 (Roth-field et al. 1978). There are several reports of isoniazid-induced lupus however, the incidence is significantly lower than that associated with hydralazine therapy, and it is difficult to estimate. Isoniazid therapy is also associated with a relatively high incidence of idiosyncratic liver toxicity (Maddrey and Boitnott 1973).

Minocycline

Minocycline is probably one of the more common drugs associated with the induction of lupus at the present time. It is interesting to note that although minocycline has been available for 30 years, its association with lupus has only recently been appreciated (Matsuura et al. 1992). There are three major idiosyncratic adverse reactions associated with minocycline therapy a serum sickness-like syndrome, liver toxicity, and a lupus-like syndrome. The serum sickness-like syndrome occurs after only approximately 2 weeks of therapy. In contrast, liver toxicity occurs after a mean of 20 months of therapy, and lupus has a mean time to onset of 28 months (range, 10 days to 10 years) (Schaffer et al. 2001). Most of the reported cases have been in women. There is a large amount of overlap between liver toxicity and the lupus-like syndrome, and many patients with elevated liver enzymes also have fever and arthralgias. Some patients report impaired concentration and poor memory, which suggest...

PBlockers

Although there have been case reports of a lupus-like syndrome associated with other P-blockers, the only two associated with a significant incidence are practolol and ace-butolol. Practolol was one of the first P-blockers, and it was associated with a lupuslike syndrome and an unusual occulo-mucocutaneous syndrome that led to its withdrawal (Raftery and Denman 1973). This led some people to suspect that it might be a class effect, and this increased suspicion about other drugs in this class. In one study, ANAs were found in eight of nine patients treated with acebutolol, and there are also case reports of acebutolol-induced lupus (Booth et al. 1982).As mentioned in the Involvement of Reactive Metabolites subsection, practolol and acebutolol are the only P-blockers that are readily metabolized to aromatic amines.

Anticonvulsants

Several anticonvulsants, such as carbamazepine, phenytoin, and ethosuximide, are associated with a low but significant incidence of drug-induced lupus (Beernink and Miller 1973, Jain 1991). The incidence of circulating ANAs in patients treated with carbamazepine is reported to be 78 (Alarcon-Segovia et al. 1972). Patients are often taking more than one anticonvulsant, so it is often difficult to be certain what drug is responsible. The aromatic anticonvulsants are also associated with a hypersensitivity syndrome in which there is some overlap with the lupus-like syndrome, but it is more acute in onset (Shear and Spielberg 1988).

Other Drugs

The list of drugs that have been associated with induction of lupus is very long. Some drugs, such as methyldopa, were not mentioned in the interest of brevity. There is also a new antiangiogenesis agent, COL-3, with a structure similar to tetracyclines, that has been reported to cause a lupus-like syndrome (Ghate et al. 2001). Estrogens have been reported to be associated with lupus, but that association is more likely due to the potentiation of idiopathic lupus. In the case of most other drugs associated with lupus, the evidence is too weak to have confidence that the association is causal.

Environmental Agents

There is no intrinsic difference between drugs and other chemicals, and it has been suggested that some fraction of idiopathic lupus is caused by environmental agents, especially aromatic amines and hydrazines (Reidenberg 1983). Adulteration of rape-seed oil with aniline led to a large number of serious autoimmune reactions in Spain (Kammuller et al. 1988). Aniline is an aromatic amine that, when heated with vegetable oils, forms fatty acid anilides. However, it is still not clear exactly which component of the adulterated oil was responsible for the syndrome or what the mechanism of the syndrome was. Other agents that have been of concern are p-aminobenzoic acid (PABA) (Mackie and Mackie 1999) and paraphenylene diamine hair dyes (Steinberg et al. 1991). Although PABA and aniline-based hair dyes can be sensitizers, there is no clear association with the induction of lupus. Exposure to specific chemicals, such as hydrazine, has also been reported to induce lupus (Reiden-berg et al....

Animal Models

It is interesting to note that although there are very few animal models of drug-induced idiosyncratic drug reactions, there seem to be more animal models of drug-induced lupus than other types of idiosyncratic drug reactions. As mentioned previously, these models include penicillamine- and mercury-induced autoimmunity in Brown Norway rats (Donker et al. 1984, Tournade et al. 1990), propylthiouracil- induced lupus in cats (Aucoin et al. 1985), and trichloroethylene-induced autoimmunity in MRL+ + mice (Kilburn and Warshaw 1992).

Controlapoptotic

Autoantigens cluster in unique apoptotic subcellular structures. Lupus autoantigens are not restricted to any specific subcellular compartment in normal cells. However, in cells dying by apoptosis induced by numerous different apoptotic stimuli, they become clustered and concentrated within small surface blebs and apoptotic bodies. In addition, phosphatidylserine, which is normally restricted to the inner surface of the plasma membrane bilayer, becomes rapidly redistributed early in apoptosis and appears at the external membrane surface. Interestingly, surface blebs of apoptotic keratinocytes bind C1q, whose collagen-like domains are the frequent ( 47 ) target of a high titer antibody response in patients with systemic lupus erythematosus. PS, phosphatidylserine Ro SSA (60 kDa), La SSB, snRNPs, Ku, and poly(ADP-ribose)polymerase (normally diffusely distributed throughout the nucleus) became concentrated as a rim around the condensing chromatin and apoptotic bodies. In...

Perniosis Chilblains

Perniosis is an inflammatory disease process commonly occurring in patients living in cold, damp geographical regions. It typically consists of erythematous papules involving the fingers, toes, nose, or ears. In general, most cases resolve within a few days and are not related to SLE. However, some lesions persist and demonstrate blister or ulcer formation. French investigators have determined that one third of the patients with chilblain lupus having this disease process for greater than 1 month have evidence of LE (Viguier et al. 2001). Another one third are patients with atypical chilblains characterized by persistent perniosis lesions who possess one to three of the preliminary criteria of the American College of Rheumatology (ACR) for the diagnosis of SLE. Follow-up of the latter patients indicated that 2 of 10 (20 ) developed SLE. Those patients with chilblain LE demonstrated that 50 of the time the chilblain lesions persisted during spring and summer. In addition, chronic...

Butterfly Rash

Lupus Rash Nasolabial Lines

A Butterfly rash in systemic lupus erythematosus. A well-demarcated, symmetrical erythema of the malar areas and the back of the nose that has progressed to the forehead and perioral skin. Note the sparing of the nasolabial folds. B Seborrheic dermatitis note the yellowish color and involvement of the nasolabial folds Fig. 11.4. A Butterfly rash in systemic lupus erythematosus. A well-demarcated, symmetrical erythema of the malar areas and the back of the nose that has progressed to the forehead and perioral skin. Note the sparing of the nasolabial folds. B Seborrheic dermatitis note the yellowish color and involvement of the nasolabial folds

Livedo Reticularis

The antiphospholipid antibodies are detected by two techniques lupus anticoagulant and anticardiolipin assays. Lupus anticoagulant activity is detected by the use of one of a variety of phospholipids-dependent in vitro coagulation assays. These assays include activated partial thromboplastin time, dilute activated thromboplastin time, colloidal silica clotting time, kaolin clotting time, and the Russel viper venom test. The anticoagulant activity detected in patients with the anti-APS is not corrected by mixing the patient's plasma with fresh normal plasma. However, the prolonged coagulation time is corrected by excess phospholipid or platelets that have been frozen and then thawed. These two assays (lupus anticoagulant and anticardiolipin) are concordant in most cases. However, it has been recognized that the APS can occur in patients possessing antibodies directed against activated protein C, protein S, thrombin III, and annexin V (for a review, see Levine 2002). All these...

Dapsone

Dapsone (4,4'-diaminodiphenylsulphone) has been in clinical use for more than 60 years. It is widely used in the treatment of a variety of infectious diseases, including leprosy and malaria, and it has some action against other parasites. In addition, it has been effective in the treatment of a diversity of cutaneous disorders, particularly those characterized by a neutrophilic infiltrate but also cutaneous manifestations of lupus erythematosus (LE), erythema nodosum, cutaneous vasculitides, pyoderma gangrenosum, bullous dermatoses, and dermatitis herpetiformis (Lang 1979, Mok et al. 1998).

Dosage

Systemic lupus erythematosus Subacute cutaneous lupus erythematosus Discoid lupus erythematosus Bullous lupus erythematosus Fig. 27.2. a 10-year-old Turkish girl with non-scarring form of discoid lupus erythematosus before therapy. b Almost total clearing of skin lesions 3 weeks after therapy with dapsone Fig. 27.2. a 10-year-old Turkish girl with non-scarring form of discoid lupus erythematosus before therapy. b Almost total clearing of skin lesions 3 weeks after therapy with dapsone

Bullous Lesions

Bullous lesions occur infrequently in patients with SLE. Blister formation may develop in some lupus lesions, especially at the periphery. This is generally associated with the presence of anti-Ro SSA antibodies. On rare occasions, blister formation, in all probability an extension of the microscopic separation at the dermal-epidermal junction, may become very extensive, especially in anti-Ro SSA antibody-positive photosensitive patients with SLE, producing cutaneous manifestations similar to toxic epidermal necrolysis (Bielsa et al. 1987). Although studies published in the 1970 s suggested that porphyria cutanea tarda was a common association with SLE, it is now believed that a causative relationship between the two diseases is unlikely. It is suspected that the use of antimalarials in the treatment of lupus precipitates or aggravates the underlying porphyrin abnormality, producing manifestations of porphyria cutanea tarda.

Clinical Experience

Although thalidomide is well known to be an effective drug for the various manifestations of cutaneous lupus, it is not widely used to treat these disorders because of its serious side effects and because it is difficult to obtain. Probably for these reasons, there are no randomized, controlled trials proving its efficacy. The available data in the literature come from a few series of patients, which show agreement regarding the good response to treatment but major differences when optimal dose, safety, and relapse rate are analyzed. Table 28.1 shows the results of the main published series. Thalidomide was used to treat DLE in the first large series published almost 20 years ago (Knop et al. 1983). Further series published in the past decade (Atra and Sato 1993, Duong et al. 1999, Kyriakis et al. 2000, Ordi et al. 2000, Sato et al. 1998, Stevens et al. 1997) also included patients with SCLE and SLE with severe cutaneous features.

AntiCD4

With DLE, including two with systemic involvement, were treated with anti-CD4. The antibody was given in two cycles of seven and four infusions, separated by an interval of 4-7 weeks with a total dose of 275 mg (two patients with DLE) or 400 or 475 mg (one patient with SCLE and two with SLE). After antibody treatment, an immediate improvement in lesional inflammatory activity and healing of cutaneous lesions was observed. Long-lasting improvement with a restoration of responsiveness to conventional anti-inflammatory agents also was noticed. Moreover, proteinuria as an index of lupus nephropathy was fully resolved. The antibody was well tolerated, and side effects such as nausea and diarrhea were controlled by application of metoclo-pramide and loperamide. Further controlled clinical trials are required to prove these very promising but preliminary results.

AntiB7

Accordingly, studies in NZB NZW mice have shown that the combined application of monoclonal antibodies directed against both B7-1 and B7-2 decreases anti-double-stranded (ds) DNA antibodies and prolongs survival. Treatment with either mAb alone did not have a similar strong efficacy. The results of first clinical trials using anti-B7 (IDEC-114) for the treatment of patients with psoriasis (Schopf 2001) and clinical studies based on these strategies in patients with lupus nephritis are forthcoming (Diamond et al. 2001).

Ljp394

LJP-394 (abetimus) is an anti-anti-ds-DNA B-cell toleragen consisting of four synthetic double-stranded oligodeoxyribonucleotides. Toleragens have been shown to suppress antibody synthesis by targeted B cells. They cross-link B-cell surface antibodies without providing the second T-cell activating signal, thereby making the B cells unresponsive. The consequence is a down-regulation of anti-ds-DNA antibody, an autoantibody presumed to be a causative factor in lupus nephritis. Therefore, a double-blind placebo-controlled study including 230 SLE patients with a history of renal disease has been performed (Alacron-Segovia et al. 2000, Furie et al. 2001, McNeely et al. 2001). Although the initial evaluation of the results indicated no efficacy in the improvement of renal disease, upon a second analysis it appeared that LJP-394 provided clinical benefit only in those patients with high levels of anti-ds-DNA antibodies. Moreover, the compound was well tolerated with a low risk for serious...

Autoimmuneneuromuscular disorders

A number of autoimmune neuroinflammatory disorders (see 6.09 Neuromuscular Autoimmune Disorders) affect either the central or peripheral nervous system. Many of these disorders are exceptionally rare such as Moersch-Woltman syndrome (stiff-man), Lambert-Eaton myasthenic syndrome, and myasthenia gravis (MG). While uncommon, these disorders tend to be highly debilitating as they directly alter neuromuscular transmission. The most common of these disorders is MG which affects an estimated 60 000 people in the USA. The primary pathology underlying MG appears to be the production of autoantibodies directed against the alpha subunit of the neuromuscular nicotinic acetylcholine receptor. Through direct interference and complement-mediated lysis of the postsynaptic muscle membrane, the autoantibodies cause disruption in the motor endplate that leads to a weakness in skeletal muscle throughout the body. The autoimmune disorder systemic lupus erythematosus (SLE) and the neuroinflammatory...

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