Cutaneous sequelae in neonatal lupus: A retrospective cohort study.

BACKGROUND: Cutaneous eruptions in neonatal lupus erythematosus (NLE) are thought to be self-resolving. Limited literature suggests cutaneous changes may persist. OBJECTIVE: To characterize cutaneous residua in NLE and identify predictors for their development. METHODS: A retrospective cohort study of patients with cutaneous NLE born between January 1980 and May 2017 was performed. Primary outcome was the proportion of patients with cutaneous residua. Secondary outcomes included associations/predictors of sequelae. RESULTS: At the last follow-up, at a mean age of 4 years (range, 0.5-18.7 years), 34% of 106 patients had cutaneous sequelae, 13% had telangiectasia, 17% had dyspigmentation, and 9% had atrophic scarring. Scarring at the last follow-up was significantly associated with the presence of skin lesions at birth (P < .001). LIMITATIONS: This study was limited by the retrospective design, short follow-up duration in a subset of patients, and small sample size. CONCLUSION: Cutaneous NLE can exhibit long-term cutaneous residua. These findings underlie the importance of accurate diagnosis, long-term monitoring, and appropriate counseling.

Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Diagnostic criteria of systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem disease characterized by vascular abnormalities, immune system activation manifested by SSc-specific autoantibodies and disturbances in fibroblast function. The clinical manifestations are highly heterogeneous and commonly include skin thickening, Raynaud's phenomenon, digital ulcers, gastroesophageal reflux disease, interstitial lung disease and cardiac diastolic dysfunction. The diagnosis of SSc in a patient with typical end-organ disease is relatively straight-forward, but is unsatisfactory because it implies that the diagnosis is delayed until irreversible tissue damage is present. Diagnostic criteria are generally designed to facilitate the clinical process and to allow early institution of therapy to relieve symptoms and possibly prevent irreversible damage. Several attempts at defining diagnostic criteria for SSc have been made in the past. Raynaud's phenomenon, SSc-specific autoantibodies and nailfold capillary abnormalities are among the most promising items likely to be retained in a final set of diagnostic criteria. The EULAR Scleroderma Trial and Research group (EUSTAR) is currently in the process of prospectively validating a set of diagnostic criteria for the very early diagnosis of SSc and results are expected in 2015.

Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis.

OBJECTIVES: The EULAR (European League Against Rheumatism) Scleroderma Trials and Research Group (EUSTAR) has identified preliminary criteria for very early diagnosis of systemic sclerosis (SSc). Our aim was to assess the prevalence of each proposed diagnostic item in a large observational patient cohort with Raynaud's phenomenon (RP). METHODS: Baseline data of 469 RP patients enrolled into the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) cohort are presented. RESULTS: 68% of all RP patients were antinuclear antibody (ANA) positive. ANA+ RP patients more frequently had previous or current puffy fingers (PuFi) (38.5% and 23.3%, p<0.01) and an SSc pattern on nailfold capillaroscopy (NC) (53.6% and 13.4%, p<0.001) than ANA- patients. Telangiectasia, current digital ulcers and digital pitting scars were also commoner in ANA+ RP patients. 38% of ANA+ patients presented with all three features, which should raise suspicion of very early SSc (ANA+RP+PuFi constitutes a 'red flag'). These patients more frequently exhibited an NC SSc pattern, sclerodactyly and telangiectases compared to ANA+ patients without PuFi. Almost 90% of patients with 'red flags' had anti-centromere or anti-topoisomerase I antibodies and/or an NC SSc pattern, and fulfilled the EUSTAR criteria for very early SSc. Previous or current PuFi were present in 23.3% of ANA- RP patients, eight of whom also had an NC SSc pattern. CONCLUSIONS: In addition to well-characterised predictive factors, PuFi is an important sign raising suspicion for underlying very early SSc in patients with RP. The relevance of PuFi in ANA- RP patients should be clarified.

[A histological and immunohistological study of vascular and inflammatory changes in rosacea]. / Étude histologique et immunohistochimique des anomalies vasculaires et inflammatoires de la rosacée.

BACKGROUND: Rosacea has a number of pathophysiological components, chief of which are vascular abnormalities and inflammation. The morphology of the dilated vessels in rosacea may indicate an increase in the number and size of lymphatic vessels. We carried out a histological and an immunohistological study to quantify these abnormalities in rosacea and compared them with those seen in lupus erythematosus. MATERIALS AND METHODS: We reviewed all cases of rosacea analysed over a 4-year period. Ultimately, we only included 86 cases in which the diagnosis could be confirmed by a dermatologist based upon histopathological correlation and follow-up. All biopsies were reviewed for histopathological features, and 25 of these were compared with 25 facial biopsies in documented cases of lupus erythematosus, using standard staining followed by immunohistochemical analysis with anti-CD3, CD4, CD8 and CD20 (lymphocytic) antibodies, anti-CD68 (histiocytic) antibodies, anti-CD31 (endothelial cell) antibodies and anti-D2-40 (podoplanin, a marker for lymphatic endothelial cells) antibodies. RESULTS: In 88% of cases of rosacea, large superficial dermal vessels of geometrical or bizarre configuration were noted, and turgescent cells and dermal edema were frequently seen. Over 75% of cases involved Demodex, including erythemato-telangiectatic subtypes. The rosacea included a mean 15 vessels/mm(2), eight of which expressed D2-40; six were greater than 30µm in diameter (mean: 103µm; maximum: 400µm), with only two of these being D2-40+. The lupus erythematosus biopsies exhibited a mean 15 vessels/mm(2), nine of which expressed D2-40; four measured over 30µm in diameter (mean: 59µm; maximum: 100µm), of which two were D2-40+. The vessels measuring over 100µm were only seen in rosacea, and notable actinic elastosis was associated in 80% of these cases. No Demodex was seen in the lupus cases. The lymphocytic infiltration consisted mainly of CD4+ T cells in both groups, but was chiefly sub-epidermal in lupus, occasionally masking the small vessels of the superficial dermis. DISCUSSION: Rosacea is characterised by large, dilated, anfractuous capillaries, which are both larger and more numerous than in lupus, although there is no difference in dermal vascular density between the two diseases. Contrary to what their form may suggest, these dilated vessels are not lymphatic. D2-40+ vessels (lymphatic), which are flatter, are found in both lupus and rosacea. The association of large telangiectasias with actinic elastosis may indicate a causative role of exposure to UV radiation. These vessels likely exhibit increased permeability, resulting in dermal edema. Inflammation is consistently present, even in the early forms, strongly suggesting a dual inflammatory and vascular mechanism.

Nail-fold capillary abnormalities are associated with anti-centromere antibody and severity of digital ischaemia.

OBJECTIVES: Advances in nail-fold capillaroscopy allow capillary abnormalities to be quantified. Our aim was to investigate, in patients with SSc, the relationships between the degree of nail-fold capillary abnormality and disease subtypes (lcSSc and dcSSc), duration of RP and the presence of (i) severe digital ischaemia (as defined by previous i.v. vasodilators, debridements or amputations), (ii) a positive ACA, (iii) clinically evident calcinosis, (iv) pulmonary arterial hypertension and (v) telangiectases. METHODS: This was a retrospective study of 176 patients. Six capillary measurements (four semi-automated and two manual) were calculated (automated width, distance between capillaries, tortuosity and derangement, and manual distance and density). Relationships between these measurements and the different clinical features of SSc were examined using multiple linear regressions (adjusted for age, sex and smoking status). RESULTS: One hundred and forty-two patients had lcSSc and 34 had dcSSc. Sixty-eight (39%) had a history of severe digital ischaemia, 66 (38%) were anti-centromere positive, 53 (30%) had clinically evident calcinosis and 26 (15%) had an estimated pulmonary artery pressure of >30 mmHg. Positive associations were found between both automated and manually measured distance between capillaries and (i) presence of severe digital ischaemia and (ii) positive ACA, and reduced density was also associated with positive anti-centromere. Patients with moderate/severe telangiectases had wider capillaries compared with those with 'mild' lesions. CONCLUSIONS: Both severe digital ischaemia and positive ACA are associated with measurable nail-fold capillaroscopic change, which has the potential of being an outcome measure for the structural microvascular disease associated with SSc-spectrum disorders.

Identification of GRASP-1 as a novel 97 kDa autoantigen localized to endosomes.

We have identified an autoantigen that is recognized by antibodies from an 18-year-old female with a history of recurrent infections who later in her clinical course developed Raynaud's phenomenon and telangiectasias. By indirect immunofluorescence (IIF), the index serum produced a unique cytoplasmic discrete speckled (CDS) staining pattern that partially colocalized with early endosome antigen 1 (EEA1) but not Golgi complex or other cytoplasmic organelles in HEp-2 cells. When HEp-2 cells were treated with 0.1 N HCl, the cytoplasmic speckled staining of the index serum was markedly decreased, suggesting that the reactive antigen was soluble. Western blot analysis showed a reactive approximately 97 kDa protein in a saline soluble protein preparation from HeLa cells. Mass spectrometric analysis of the excised 97 kDa band that was immunoprecipitated from HeLa cell extracts identified GRASP-1 as a possible target. The index serum and anti-GRASP-1 antibodies colocalized to structures in the cytoplasm of HEp-2 cells. Synthetic peptides representing the full-length GRASP-1 protein were used to identify reactive epitopes. Like many other cytoplasmic autoantigens, GRASP-1 has numerous coiled-coil domains throughout the protein with the exception of short segments at the amino and carboxyl terminus.

[Immunopathogenetic, clinical features and treatment of external exudative Coats' retinitis]. / Immunopatogeneticheskie, klinicheskie osobennosti i lechenie naruzhnogo éksudativnogo retinita Koutsa.

The findings of comprehensive clinical and immunopathogenetic examinations of 42 patients with external exudative Coats' retinitis showed the significance of infection in the etiopathogenesis of disease and helped identify the etiology, mainly infectious, in 47.6% patients, which correlated with case histories indicating foci of chronic infection and type I immunological insufficiency. Toxoplasma infection was the predominant etiological factor (38 cases). The predominant clinical symptoms were solid exudation, vascular changes, hemorrhages, vitreous involvement, and exudative detachment of the retina. Changes in the immune status were as follows: shifts in T- and B-immunity, impaired complex formation, in some cases selected deficit of IgA. Association of Coats' retinitis with erythrocytic phenotype B(III) was detected in 44% patients (p < 0.02); carriers of this blood group are at a high risk (RR 11.16) of the disease. The treatment was carried out with consideration for etiology, immunopathogenesis, and clinical picture and was supplemented by argon laser coagulation, if indicated.

[Retinal vasculopathy associated with Berger's IgA nephropathy]. / Retinale Vaskulopathie assoziiert mit Bergers IgA-Nephropathie.

AIM: Ophthalmological complications associated with Berger's IgA nephropathy comprise scleritis, episcleritis, keratoconjunctivitis as well as anterior uveitis. We present a new association of IgA nephropathy with a retinal vasculopathy. METHODS: Presentation of two clinical cases. RESULTS: Two patients presented with hematuria and epistaxis associated with a retinal vasculopathy characterised by teleangiectasies, capillary occlusion with retinal hemorrhages, neovascularisations and macular edema with decreased visual acuity. Fluorescein angiography showed zones of non-perfusion as well as vasculitic changes. A general medical exam revealed a normal arterial pressure but a slightly elevated creatinine. Immunological investigations for the presence of antibodies showed no positive results. Renal biopsy demonstrated mesangial proliferations with diffuse deposits of IgA. Over the course of a 2 year follow-up some of the retinal changes regressed under treatment with cortisone and visual acuity returned to normal. The teleangiectasies showed no progression. CONCLUSION: Berger's IgA nephropathy can be associated with a retinal vasculopathy which may be due to local deposition of IgA immune complexes in the retinal vessels.

Generalized essential telangiectasia in a patient with Graves' disease: should the spectrum of autoimmune diseases associated with generalized telangiectasia be expanded?

Generalized essential telangiectasia (GET), as originally described, is not associated with any underlying disease. Although patients with GET lack the typical periungual telangiectases associated with autoimmune collagen vascular diseases, these patients may have an underlying autoimmune process. We present a patient with a history of Graves' disease and low-titer anti-nuclear antibodies, who developed rapidly progressive generalized telangiectases. The gender and age of the majority of patients with GET fit well within the demographics of most autoimmune diseases. The documented occurrence of an autoimmune disease in several of the limited number of patients previously diagnosed with GET provides additional evidence that GET may be associated with an underlying autoimmune disease.

Especificidad molecular a proteínas CENP en sueros anti-centrómero / Molecular specificity to CENP proteins in anti-centromere sera

Se estudió la reactividad molecular a proteínas CENP, en sueros con especificidad anticentrómero, utilizando extractos de células HEp-2, por la técnica de Western blot, las bandas inmunorreactivas se revelaron por autorradiografía. En 1691 sueros en los que se determinaron anticuerpos, por inmunofluorescencia indirecta, 11 resultaron con patrón anti-centrómero, de éstos, siete reconocieron bandas de CENP en w. blot, los antígenos más frecuentes detectados fueron CENP-B y CENP-C. El estudio a nivel molecular constituye una alternativa fina para la determinación de la especificidad de los autoanticuerpos

Anti-centromere antibody and CREST syndrome in patients with primary biliary cirrhosis.

Anti-centromere antibodies (ACA) in 41 sera from patients with primary biliary cirrhosis (PBC) were analyzed by an immunoblotting method and the correlation between the presence of ACA and the clinical features in these PBC patients was studied. In 10 of 16 ACA-positive PBC patients, one or more clinical features of CREST syndrome (PBC-CREST) were found. Statistical differences were observed in age at disease onset, serum levels of IgM and total bilirubin and titer of anti-M2 antibody, between PBC-CREST patients and the PBC patients without CREST symptoms (PBC-non CREST). By immunoblotting analysis, three major epitopes of ACA were identified at 18 kD, 80 kD and 140 kD polypeptides. The 18 kD polypeptides were detected in all 16 ACA-positive PBC patients. From these results, it is suggested that ACA-positive PBC-CREST patients can be separated from ACA-negative PBC-CREST and PBC-non CREST patients.

Systemic mastocytosis treated with histamine H1 and H2 receptor antagonists.

A case of systemic mastocytosis with skin characteristics of telangiectasia macularis eruptiva perstans is reported. Systemic involvement was confirmed as a combination of highly increased urinary excretion of methyl imidazole acetic acid (Melm AA) and increased amounts of mast cells in skin, liver and colon transversum. Treatment with cimetidine (H2 receptor antagonist) resulted in diarrhea, however, the addition of cyproheptadine (H1 receptor antagonist) was beneficial in amelioration of the cutaneous symptoms of mastocytosis. The excretion of Melm AA was unchanged during treatment. After 7 months of continuous cimetidine and cyproheptadine treatment no side effects were observed.

[Waldenstrm macroglobulinemia presenting in the form of cold urticaria and cold purpura]. / Hideg urticaria és hideg purpura képében jelentkezö makroglobulinaemia Waldenström.

A Waldenström macroglobulinemia case, manifested in the form of non-specific skin-symptoms (cold urticaria and cold purpura) is described in a 37 years old female patient. As new skin-symptoms progressive telangiectasia and naevi aranei could be observed. Involvement of skin may be explained by macroglobulins with kryoprotein properties, making early diagnosis possible at the same time.

Clinical association of autoantibodies to fibrillarin with diffuse scleroderma and disseminated telangiectasia.

Circulating autoantibodies against a variety of nuclear and nucleolar antigens are characteristic serologic findings in systemic scleroderma. Some of these antibodies correlate with clinical subsets of the disease. We describe three patients with systemic scleroderma and high autoantibody titers against U3 ribonucleoprotein-associated fibrillarin, a recently identified 34 kD nucleolar protein. These patients showed a progressive course with multiple organ and diffuse skin involvement with disseminated telangiectasia.

Anticentromere antibody positive CREST syndrome associated with polyarthritis, renal impairment and mixed cryoglobulinaemia.

We describe a 63-year-old female who developed the CREST syndrome within two years. Even though she was anticentromere antibody positive, her illness followed a very aggressive course and was associated with severe polyarthritis, renal impairment, hypocomplementaemia and mixed cryoglobulinaemia.

Coexistence of CREST syndrome and primary biliary cirrhosis. Serological studies of two cases.

Two patients with characteristic features of CREST syndrome and primary biliary cirrhosis are reported. Sera of both patients contained autoantibodies to centromere and mitochondrial antigens. Immunodiffusion analysis identified the specificities of precipitating antibodies to mitochondria of the first case as anti-M-A and M-C, and of the second case as anti-M-A and M-B antibodies. Simultaneous occurrence of 2 marker antibodies in an individual patient indicates that the 2 patients reported here have CREST syndrome and primary biliary cirrhosis, both of which are considered as a distinct clinical entity.