In contrast to skin manifestations associated with overt SCLE and SLE, patients with the different subtypes of CCLE will primarily present to dermatologists as long as systemic manifestations are missing. Once internal organ involvement has occurred, these patients will be referred to general practitioners or rheumatologists for analysis of systemic disease. Alternatively, general practitioners or rheumatologists may ask dermatologists to search for typical skin manifestations of LE in a suspected patient or to evaluate present skin symptoms as typical for or related to LE. In cases of CCLE, first line efforts will head at their definite diagnosis which as already outlined above may be sometimes difficult to establish.
Case history has to focus on LE-related symptoms like photosensitivity, arthralgia or arthritis, diffuse or areata-like alopecia, Raynaud's phenomenon, Sicca symptoms, morning stiffness of joints, thrombosis, spontaneous abortion, atypical pneumonia and carditis as well as neurological disorders. To support clinical diagnosis, histological as well as immunohistochemical examinations of skin lesions will be performed. Depending on the stage and acuity of LE, the typical histological findings include epidermal hyperkeratosis, epidermal atrophy, basal cell degeneration, thickening of the epidermal basement membrane, liquefaction degeneration and mononuclear cell infiltrate at the dermo-epidermal junction as well as around blood vessels and adnexial structures. The dermato-histological features of different LE types
(ACLE, SCLE, DLE) may be very similar (Sontheimer and Provost 1996; Acker-man 1997). Often these parameters do not allow to clearly distinguish the different entities apart from quantitative differences in epidermal or especially follicular hyperkeratosis which are characteristic for DLE. Special histological features can be found in LE tumidus with its characteristic abundant, partly focal deposition of mucin among collagenous fibers of the reticular dermis. Lupus panniculitis presents with a lobular pattern of perivascular and periad-nexial mononuclear infiltration and partially necrobiotic changes of fatty tissue with fibrinoid deposits as well as focal calcinosis in the deep dermis.
The characteristic findings of direct immunohistochemical examination of lesional skin are granular immune deposits of mostly IgG, IgM and complement factor C3 in a continuous line along the dermo-epidermal junction (so-called lesional lupus band test) (George et al. 1995; Cardinali et al. 1999). They will be only found in lesions of more than four to six weeks duration, an aspect which argues against their pathogenic relevance and the immediate involvement of immune complex mechanisms. Furthermore, the incidence of positive lupus band tests is higher in biopsies from upper body sites that is more likely in those from the face than in those from the trunk. However, neither does their absence exclude CCLE nor is their presence specific for LE. They may be found in sun-damaged skin, rosacea and polymorphic light eruption, often with deposits of IgM only. The significance of immune deposits in non-lesional skin (non-lesional lupus band test) is much debated (George et al. 1995; Cardinali et al. 1999) and seems specific for SLE when IgG and two additional immunoglobulin subtypes (IgG, IgM, IgA) are detected. Skin biopsies for non-lesional skin may be taken from the the inner aspect of the upper arm (sun-protected) and the extensor aspect of the forearm (sun-exposed). In CCLE with no extracutaneous manifestations these biopsies should be negative. The findings of the lupus band test have to be carefully interpreted together with other serological examinations. Epidermal dust-like particles in a specific fine speckled pattern which are generally associated with SCLE and anti- SS-A antibodies are rarely detected in DLE and may indicate more severe disease with progression to systemic manifestations (Sontheimer and Provost 1996; Norris et al. 1996). In patients with high titered antinuclear antibodies, especially anti-U1-RNP (which is typically associated with mixed connective tissue disease), positive epidermal nuclei can be found by direct immunofluorescence microscopy. This phenomenon most probably derives from in vitro binding of high titer or high affinity antibodies. In vivo penetrating the cell membrane autoantibodies may be found as well. However, their significance for disease manifestation as well as diagnostic procedures remains to be elucidated (Golan et al. 1997). Using specific monoclonal antibodies, the membrane attack complex (C5b-9) could be demonstrated in the epidermis of different subsets of CCLE and may allow further distinction (Magro et al. 1996). In lupus profundus as well as in SLE granular deposits of IgG and C3 may be occasionally found in dermal vessel walls indicating immune complex vasculitis.
Serological tests are critical for the confirmation of CCLE. Antinuclear antibodies of high titers and characteristic specificity will rarely be found without systemic manifestation. They may however be present in cases of generalized DLE which in turn has a greater risk to progress to SLE. Anti-Ro(SS-A) antibodies can sometimes be detected by ELISA techniques, may however lack precipitating activity, i.e. immunodiffusion techniques are negative (Provost et al. 1996). Anti-DNA-antibodies are negative in classical DLE and other subsets of CCLE and if present indicate systemic disease (Watanabe et al. 1995; Provost et al. 1996; Sontheimer and Provost 1996; Tebbe et al. 1997). Anti-cardiolipin antibodies are mostly not detectable. They may be found in cases of lupus panniculitis and chilblain lupus indicating secondary antiphospholipid syndrome and progession to systemic disease (Ruffati et al. 1995). Similarly, tests for complement consumption (e.g. CH50 test), detection of complement fragments and circulating immune complexes will mostly be negative or only slightly altered and should only be performed in cases of suspected systemic disease. Serum levels of other serological molecules like soluble adhesion markers and soluble IL-2 receptor are related to disease activity (Sontheimer and Provost 1996), but have not yet been established as routine parameters.
Apart from the above examinations, basic clinical routine laboratory tests should be performed to exclude anemia, leukopenia, renal involvement (pro-teinuria, hematuria) and systemic inflammation. Accordingly, blood sedimentation rate (BSR), blood cell count, hepatic enzymes, urine sediment and serum immunoglobulins should be checked. Pathologic findings are substantiated by further tests if necessary. Clinical tests like chest X-ray and evaluation of organ involvement (e.g. in ophthalmology, neurology, cardiology) should be performed based on case history or pathologic results of physical or laboratory exams. The indication for routine testing of cutaneous sensitivity to ultraviolett light as well as photoprovocation is much debated in CCLE. However, the impact of these exams with regard to stringency of sun protection and consequences for life-style supports their usefulness in the clinical routine (Kind et al. 1993; Sontheimer and Provost 1996, Kuhn et al. 2001).
CCLE patients should be monitored at 6 to 12-months intervals for further signs of systemic disease, especially when anemia or leukopenia, persistent high ANA titers or elevated blood sedimentation rates are found. Based on these clinical and laboratory findings, disease activity can be quantitated using the Systemic Lupus Activity Measure (SLAM) (Parodi et al. 2000) which may be a valuable parameter to monitor the patients.
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