Classification of the wide variety of autoimmune diseases that can occur before or after the onset of Sjögren’s syndrome (SS) is currently debated within the conventional SS criteria or as primary SS (pSS) developing autoimmune disease or as ‘associated-overlap’ with other systemic autoimmune diseases. There is also debate on whether or not to consider annular polycyclic subacute cutaneous lupus erythematosus (SCLE) and annular erythema associated with Sjögren's syndrome (AESS) as a spectrum linked to Ro-SSA and/or La-SSB auto-antibodies (SSA/SSB auto-ab). We present the case of a 55-year-old female patient, with pSS positive for SSA and SSB auto-ab, who developed chronic relapsing polymyositis and atypical annular non-polycyclic SCLE lesions resembling AESS, which seemed to suggest a common spectrum. While a chronic-progressive polymyositis may be generally accepted as a relatively rare myositis complicating pSS, interpretation of annular lesions of non-systemic SCLE in SS patients might actually be underestimated as pSS skin manifestation likely related to SSA/SSB auto-ab.

Nodular scleroderma is a rare complication of systemic sclerosis; the pathogenetic implications are still unknown, although many factors are supposed to play a role in lesion development. We report the case of a young woman suffering from systemic sclerosis, who developed nodular lesions during therapeutic management with D-penicillamine and plasmapheresis. In order to better understand the essence of this disease, we examined all the possible pathogenetic mechanisms that could be implicated in nodular lesion development.

Xerosis is a common skin condition characterized by roughness, scaling, loss of elasticity and often discomforting sensations of itching and burning. Xerosis is a specific component of various dermatological diseases (atopic dermatitis, allergic and irritative contact dermatitis, asteatotic eczema) and/or a consequence of systemic or topical treatments. Xerosis is also a common manifestation of frequent reating washing enhanced by winter weather and represents a "paraphysiological" condition in elderly (>70 years). When one of these conditions is present xerosis can be defined as secondary, while it is defined as "idiopathic" or constitutional when it appears independently of age or any well-know pathological or physiopathological cause. Xerosis is the most common skin manifestation in primary Sjögren syndrome (pSS) (23–67%) [[1]Ueki H. Ingaki Y. Hamasaki Y. Ono M. Dermatologische manifestations des Sjögren-syndrome.Hautarz. 1991; 42: 741-747PubMed Google Scholar]. In our previous study we documented xerosis in 54 of 62 pSS [[2]Bernacchi E. Amato L. Parodi A. Cottoni F. et al.Sjögren's syndrome: a retrospective review of the cutaneous features of 93 patients by the Italian Group of Immunodermatology.Clin Exp Rheumatol. 2004; 22: 55-62PubMed Google Scholar]. Therefore, Sjögren syndrome (SS) may be considered as atopic dermatitis a disease characterized by secondary xerosis. Since the pathogenetic mechanisms of xerosis in pSS patients are not well-known, we conducted a histopatological examination of xerotic skin to evaluate epidermal, dermal, sebaceous and sweat glands alterations and immunohistochemical investigations to evaluate the epidermal expression of specific molecules (cytokeratins, involucrin and loricrin) involved in keratinocyte differentiation and proliferation. Moreover, to study the skin barrier function of xerotic skin in pSS patients, we employed corneometry and evaporimetry as non-invasive methods to detect stratum corneum water content and trans epidermal water loss (TEWL). Thirteen female patients (mean age 55 ± 4 years) affected with pSS were selected. Diagnosis was done on the basis of clinical, histopathological, immunopathological and serological evaluation, according to the European Community Study Group criteria [[3]Vitali C. Bombardieri S. Moutsopoulos M.H. et al.Assesment of the European classification criteria for Sjögren syndrome in a series of clinically defined cases: result of a prospective multicentre study.Ann Rheum Dis. 1996; 55: 116-221Crossref PubMed Scopus (475) Google Scholar]. Cutaneous xerosis present in all 13 patients was defined on the basis of both objective signs, such as roughness, scaling, cracks and fissures using European Group for Efficacy Measurements on Cosmetic and other Topical Products (EEMCO) guidelines [[4]Serup J. EEMCO Guidelines. Evaluation of dry skin (xerosis) and ictyosis. Clinical score systems.Cosm Technol. 1999; 2: 9-13Google Scholar] and subjective symptoms (such as pruritus, dryness and pinprick-like sensation). Xerosis was assessed in the deltoid areas, shoulders and external limbs by two independent observers. The detection of stratum corneum water content was performed by means of a capacitance device (Corneometer, CM 420, Courage and Khazaha, West Germany) [[5]Courage W. Hardware and measuring principle: corneometer.in: Elsner P. Berardesca E. Mailbach H. Bioengeneering of the skin: water and the stratum corneum. CRC Press, Boca Raton1994: 171-175Google Scholar]. We employed an evaporimeter (Servomed-Milano, Italy) for measuring basal TEWL [[7]Ellman P. Weber F.P. Goodier TE.W. A contribution to the patology of Sjögren's disease.Quart J Med. 1951; 20: 33-42PubMed Google Scholar]. These determinations were obtained in the morning, from March to June, after a resting period of 15 min and in presence of standard environmental conditions (room temperature between 19 and 21 °C, relative humidity 40–50%) for each of the 13 pSS patients and relative 11 female healthy controls (mean age 53 ± 6 years). These functional investigations were done at the same time and on pre-estabilished cutaneous areas: deltoid region, dorsal surface of the (right) hand, dorsal surface of the forearm, antero-lateral surface of the thigh and forehead. TEWL was expressed in g/m2 h, stratum corneum water content in Corneometer Units [5Courage W. Hardware and measuring principle: corneometer.in: Elsner P. Berardesca E. Mailbach H. Bioengeneering of the skin: water and the stratum corneum. CRC Press, Boca Raton1994: 171-175Google Scholar, 6Pinnagoda J. Tupker R.A. Agner T. Serup J. Guidelines for transepidermal water loss (TEWL) measurement.Contact Dermatitis. 1990; 22: 164-178Crossref PubMed Scopus (1080) Google Scholar]. Four female pSS patients (mean age 52 ± 3 years) of the previous group with severe xerosis and four healthy female control subjects (mean age 50 ± 5 years) were selected for immunohistochemical investigations. A punch biopsy was performed on the deltoid area of the patients and control subjects after informed consent. Every punch biopsy (5 mm diameter) was subdivided into two parts: one was employed for immunohistochemical investigations the other was used for histological examination (hematoxylin and eosin). Immunohistochemistry was employed to evaluate epidermal cytokeratins, involucrin and loricrin (the major molecules involved in keratinocytes proliferation and differentiation). The following primary antibodies were used: anti-Ki 67 (1:30; DAKO, Glostrup, Denmark) to evaluate the epidermal proliferation rate, anti-MNF 116 (1:50; DAKO, Glostrup, Denmark) directed against epidermal basal cytokeratins 5 for the evaluation of epidermal differentiation, anti-34βE12 (directed against basal (k1–k5) and suprabasal (k10–k14) epidermal cytokeratines (1:50; DAKO, Glostrup, Denmark), anti-involucrin (1:100; Novocastra Laboratories Ltd, Newcastle upon Tyne, UK) and anti-loricrin (1:500; BabCO, Richmond, CA, USA) to evaluate the terminal phase of keratinocytes differentiation. Two independent and "blinded" observers evaluated serial sections. No pathological alterations were detected in the group of the 13 pSS patients studied with corneometry and evaporimetry, because for each pSS cutaneous region examinated the mean values obtained were the same as those registered in our control groups and as those previously reported by other authors for healthy skin. Only in deltoid area TEWL values were significantly (p = 0.037) lower (Fig. 1). Slight epidermal hyper-ortokeratosis and dermal elastosis were noted in the pSS biopsy specimen examined. In particular no morphological alterations or reduction in number of sebaceous and sweat glands were demonstrated. Table 1 demonstrates that all four female pSS patients selected for immunohistochemical investigations showed an intense and marked staining with Ki 67 of the basal and spinous layers. We also demonstrated increased epidermal differentiation, revealed by intense staining of the basal and spinous layers with monoclonal MNF 116 (specific for epidermal basal cytokeratin 5). The expression of 34βE12 (specific for epidermal basal 1–5 and suprabasal 10–14 cytokeratins) was similar both in pSS patients and in the control subjects. The final phase of keratynocytice differentiation also appeared altered in the pSS patients, with involucrin expression not only in the granulous, but also in the highest part of the spinous layer. Loricrin was equally expressed at the level of the granulous layer in pSS patients and in control subjects.Table 1Immunohistochemical characterization of cytokeratins, involucrin and loricrin in pSS patients and control subjects.pSS patientsControl subjects(4 pt.)1234Ki 67BL + SLBL + SLBL + SLBL + SLBLMNF 116BL + SLBL + SLBL + SLBL + SLBL34βE12BL + SLBL + SLBL + SLBL + SLBL + SLInvolucrinSL + GLSL + GLSL + GLSL + GLGLLoricrinGLGLGLGLGLBL: staining of basal layer; SL: staining of spinous layer; GL: staining of granulous layer. Open table in a new tab BL: staining of basal layer; SL: staining of spinous layer; GL: staining of granulous layer. In conclusion our studies demonstrate that xerosis in pSS is not related to a chronic inflammatory atrophy of sweat glands [[7]Ellman P. Weber F.P. Goodier TE.W. A contribution to the patology of Sjögren's disease.Quart J Med. 1951; 20: 33-42PubMed Google Scholar] or their functional alterations with consequent reduction of sweat rate (resulted normal or higher than normal control [8Rees J.I. Pal B. Stimulated eccrine gland function in primary Sjögren syndrome.Clin Exp Dermatol. 1989; 14: 191-193Crossref PubMed Scopus (9) Google Scholar, 9Katayama I. Yokozeka H. Nishioka K. Impaired sweating as an exocrine manifestation in Sjögren's syndrome.Br J Dermatol. 1997; 133: 716-720Crossref Scopus (41) Google Scholar]. Therefore, on the base of our studies cutaneous xerosis in pSS, unlike xerophtalmia and xerostomia, is not a feature of a chronic autoreactive lymphocytic exocrinopathy. Instead xerosis in pSS seems to be related to peculiar biochemical alterations of epidermis (increased epidermal proliferation and perturbation of epidermal differentiation) very similar to those detected by Engelke et al. [[10]Engelke M. Jensen J-M. Ekanayake-Mudiyanselage S. Proksch E. Effects of xerosis and agening on epidermal proliferation and differentiation.Br J Dermatol. 1997; 137: 219-225Crossref PubMed Scopus (125) Google Scholar] in "idiopathic" xerotic skin of the elderly. The alterated expression of cytokeratins and premature demonstration of involucrin, are presumably the biochemical basis of xerosis in pSS able to explain the alterations of epidermal barrier function and consequent decreased TEWL values especially in cutaneous areas (as deltoid surfaces) where the xerosis is more accentuated.

OBJECTIVE:Various cutaneous manifestations have been described (xerosis, eyelid dermatitis, angular cheilitis, cutaneous vasculitis and annular erythema) in Sjögren's syndrome (SS), but so far only three studies on large numbers of SS patients have been carried out. The frequency of cutaneous manifestations and their association with specific clinical or immunological parameters have never been studied. The aim of the Italian Group of Immunodermatology was to evaluate these associations in a large number of SS patients.METHODS:A retrospective review was performed on 93 patients with SS followed over a ten-year period (1990-2000) at 6 Italian dermatological centers. They were subdivided into two groups, 62 with primary SS and 31 with secondary SS, and the frequency of cutaneous manifestations and specific antibodies was determined and compared between them.RESULTS:We found significantly higher levels of xerosis (p = 0.009) (56.4% versus 25.8%) and angular cheilitis (p = 0.017) (38.7% versus 16.1%) in primary SS patients than in those with secondary SS. A significant association of xerosis with anti-SSA + SSB (p = 0.033) antibodies was also demonstrated. Eyelid dermatitis and pruritus were common but less specific cutaneous symptoms. Annular erythema was found more often in primary (6.45%) than in secondary (3.2%) SS and was associated with SSA + SSB antibodies in 75% of the cases. Cutaneous vasculitis was present in 30.6% of primary SS (manifesting as palpable purpura in 84%) and in 29.3% of secondary SS cases.CONCLUSION:Xerosis is the most frequent and characteristic cutaneous manifestation of primary SS. It is not linked to decreased sebaceous or sweat gland secretion, but more probably to a specific alteration of the protective function of the stratum corneum. Angular cheilitis is a common but less specific skin lesion in SS and is associated with xerosis and xerostomia.

We have evaluated the incidence of lupus erythematosus (LE)-specific skin disease in 186 patients with LE, seen retrospectively over a 10-year period at our Dermatology Department and determined the correlation of LE-nonspecific skin disease in patients with systemic involvement. Chronic cutaneous LE (CCLE) with classical discoid lesions (localized, 70%; generalized, 30%) was the most common cutaneous manifestation (72.5%). Subacute cutaneous LE (SCLE) represented only 8% of LE skin disease (annular-polycyclic type, 73%; papulo-squamous type, 27%). Acute cutaneous LE (ACLE) was detected in 15% of our patients: the butterfly erythema was the most frequent skin lesion (96%) while only one case of bullous LE and one case of widespread maculo-papular eruption in association with malar erythema were demonstrated. In 8 patients no LE-specific skin lesions (lupus sine lupo) were found. LE-nonspecific skin lesions were found in 31% of our patients with systemic LE (SLE): Raynaud's phenomenon was found in 23/58 (39.6%), cutaneous small vessel leukocytoclastic vasculitis in 8/58 (13.7%), nonscarring alopecia in 18/58 (31%), lupus pernio in 6/58 (10.3%), hemorrhagic lesions in 4/58 (6.8%), livedo reticularis in 5/58 (8.6%), mucosal ulcers in 3/58 (5.1%) and periungual telangiectasia in 12/58 (20.6%) SLE patients. LE-nonspecific skin lesions are detected only in patients with SLE and usually in the active phases of the disease.

Background: Subacute cutaneous lupus erythematosus (SCLE) is a distinct subset of cutaneous lupus erythematosus clinically characterized by psoriasiform and/or annular lesions and by a mild or absent systemic involvement. Objective: The Italian Group of Immunodermatology of the Italian Society of Dermatology and Venereology reviewed the cases of SCLE seen in 10 years (1987–1996). Patients: Forty-six women and 12 men have been retrospectively studied, 42% had annular lesions, 39% psoriasiform ones and 16% both. Results: Lesions were mainly localized on the neck and face and relapsed in spring and autumn. Seventeen patients had 4 or more American College of Rheumatology criteria and could be classified as having systemic lupus erythematosus. The most frequent histopathological alterations were epidermal atrophy, hydropic degeneration of the basal layer and perivascular lymphocytic infiltrate. Deposits of immunoglobulins and C3 at the dermo-epidermal junction on the clinically involved skin were present in 86% of the patients. Dust-like particles in the epidermis were only found in 3% of cases. Anti-Ro/SSA antibodies were found in 71% of the cases and anti-dsDNA only in 5% of cases. Conclusions: SCLE is a particular subset of cutaneous lupus erythematosus with peculiar clinical and immunopathological features.

An association between mixed cryoglobulinaemia (MC) and hepatotropic viruses, chiefly hepatitis C virus (HCV), has been widely reported. The presence of HCV genomic sequences or HCV-related viral proteins in the serum, purified cryoglobulins, peripheral blood mononuclear cells and into several tissues has suggested an important triggering role for HCV in MC patients. However, only few reports investigated the presence of HCV in cutaneous vasculitis and its potential pathogenetic role. Biopsies of cutaneous purpuric lesions from 5 MC female patients (aged from 40 to 80 years) were carried out for virological and histopathological evaluation. A leukocytoclastic vasculitis pattern was found in 4/5 subjects, while the presence of HCV RNA was detected in 3/5. In only 3 cases biopsy specimens were sufficient for immunohistochemical and direct immunofluorescence (DIF) studies. Immunohistochemical evaluation was performed by means of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) immune-complexes. In the same skin specimen APAAP and DIF findings were compared with the presence/absence of HCV genomic sequences (PCR technique). In 1 MC patient, the detection of HCV-RNA was associated to a prevalent CD8(+) T suppressor pattern with a perivascular and subjunctional distribution as well as an intense expression of second class (HLA-DR) and intercellular adhesion (ICAM-1) molecules on basal keratinocytes, endothelial cells and perivascular infiltrate. These findings suggest a marked inflammatory activation that spreads from endothelial cells to keratinocytes and Langerhans cells. In the 2 HCV-RNA negative specimens the scanty immunopathological staining could indicate a residual activity due to the previous inflammatory event triggered by cryoglobulins. The deposition of circulating HCV-containing immune complexes (CIC) in the skin could be the initial pathogenic event for cryoglobulinemic vasculitis; subsequently CIC could spread from the vascular bed to the perivascular tissue and then could be very rapidly eliminated. If confirmed in larger patients' series these findings could definitely demonstrate a direct role of HCV in the pathogenesis of cryoglobulinemic vasculitis.

We describe a patient with systemic lupus erythematosus (SLE) who exhibited severe cutaneous involvement characterized by the simultaneous presence of acute, subacute and discoid lesions in association with anti-Sl antibodies. After she failed to respond to chloroquine, medium to low dose steroids, steroid pulses, retinoids and cyclophosphamide, the patient was treated with Dapsone and a dramatic improvement in the cutaneous lesions was seen after only one month.

Linear IgA bullous dermatosis (LAD) is an acquired, heterogeneous, subepidermal blistering disease characterized by linear IgA deposits at the dermoepidermal basement membrane zone (BMZ), often with circulating IgA antibodies to the BMZ. The pathogenetic mechanism, possibly related to the immunophenotype of infiltrating cells, as well as the potential role of cytokines in determining bullous lesions, have not yet been elucidated. An immunohistochemical study was performed with a large panel of monoclonal antibodies [to CD3, CD4, CD8, CD25, CD1a, CD30, CD54, CD50, endothelial leucocyte adhesion molecule-1, vascular cell adhesion molecule-1, myeloperoxidase (MPO), eosinophil cationic protein EG1 and EG2, tryptase, HLA-DR, human interleukin (IL)-3, human IL-5, human IL-8, human IL-4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte/macrophage colony-stimulating factor] using the alkaline phosphatase-antialkaline phosphatase procedure on lesional and perilesional skin of nine patients (one male, eight female; age range 8 months-80 years) with clinical, histological and immunofluorescent proven LAD. The predominant infiltrating cells, distributed mostly inside and below the bullae, were neutrophils and eosinophils which showed intense activation (MPO +, EG1 +, EG2 +). The lymphocytic infiltrate, consisting principally of CD4 +, HLA-DR + and CD30 + T cells, had a predominantly perivascular distribution. Proinflammatory cytokines, such as TNF-alpha and IFN-gamma, showed a moderate focal expression on the dermal perivascular sites; IL-8 was found to have a particularly intense staining on all the epidermal cell layers and at perivascular and vascular sites. Other cytokines, such as IL-4 and IL-5, showed a prevalent intracytoplasmic staining on some cells of the dermal infiltrate (probably mastocytes and lymphocytes), and at the dermal-epidermal separation sites there was also an intense scattered distribution of IL-5. The specific tissue lesions of LAD may be the consequence of the IgA deposits at the BMZ and also of the release of these cytokines together with tissue damage enzymes derived from neutrophils or eosinophils.

In view of the critical role of dendritic cells in immune mediated skin diseases, we have investigated the membrane antigen patterns and ultrastructure of cutaneous dendritic cells in eight patients with chronic discoid lupus erythematosus and five with subacute cutaneous lupus erythematosus. In the lesional epidermis, the expression of HLA‐DR antigens by epidermal dendritic cells was reduced, as compared with perilesional, clinically normal skin. In addition, only few CD1a+ dendritic cells (Langerhans' cells), along with some CD11c+ and CD14+ cells (presumable precursors of Langerhans' cells), were found in atrophic areas of lesional epidermis. In contrast, the number of Langerhans' cells in non‐atrophic areas of lesional epidermis was similar to that in perilesional skin. On electronmicroscopy, epidermal Langerhans' cells appeared depleted of organelles and dendrites and contained tubuloreticular inclusions. In the lesional dermis, both CD1a+ and CD36+ dendritic cells were found, associated with CD4+ and CD8+ T‐cells, respectively. Moreover, CD11c+ and CD14+ cells were found around capillaries in the papillary dermis on electronmicroscopy. Indeterminate cells (dendritic cells with features of Langerhans' cell lineage, but apparently without Birbeck granules) and dendritic macrophages were found, associated with lymphocytes and mast cells. No cells with intermediate/transitional features between these two dendritic cell types were found. Conversely, peculiar dendritic cells—with short and blunt dendrites and cytoplasm containing many flat, rough cisternae, moderately well developed Golgi apparatus and no lysosomes—were found in the same location as the CD11c+ and CD14+ cells identified by light microscopy. These findings might be interpreted as follows: 1 the alterations in cytological differentiation and expression of functionally meaningful molecules by epidermal Langerhans' cells in cutaneous lupus erythematosus lesions suggest an impairment of their immunological efficiency; 2 in the lesional dermis of cutaneous lupus erythematosus, a CD4+ T‐cell/CD1a+ dendritic cell‐based, delayed‐type immune response is possibly modulated by a suppressor T‐cell circuit in which CD36+ dendritic cells may act as accessory cells; 3 CD11c+ and CD14+ cells with peculiar ultrastructure are possible precursors of both CD1a+ indeterminate cells and CD36+ dermal dendrocytes in the dermis.

Following a broad review of the literature referring to the histopathological clinical, immunological and immunogenetic characteristics of a particular variety of recently identified cutaneous lupus erythematosus, namely subacute lupus erythematous, the results of immunopathological studies in 11 patients (6 of whom presented the ring polycyclic variety and 5 the psoriasiform variety) are reported. Serum and skin samples were compared in both varieties and it was noted that there is: 1) a more marked incidence of hypocomplementemia and the presence of immune circulating complexes in the ring-polycyclic variety; 2) a more frequent demonstration of IgG and C at the dermo-epidermic junction and on the edge of superficial derma vessels in the same variety. These findings are interpreted as being the consequence of a more frequent and severe systemic (and above all renal) impairment in the ring-polycyclic variety.