Elisabeth Aberer

Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma.

RATIONALE Pulmonary arterial hypertension is associated with impaired exercise capacity and decreased survival in patients with scleroderma. Randomized controlled studies showed significant benefit of targeted therapies in patients with a resting mean pulmonary arterial pressure (MPAP) greater than 25 mm Hg. The clinical relevance of pulmonary arterial pressure values in the upper normal range is unknown. OBJECTIVES To examine the clinical relevance of pulmonary arterial pressure in scleroderma patients. METHODS After a noninvasive screening program, 29 patients with systemic sclerosis without significant lung fibrosis and without known pulmonary arterial hypertension underwent right heart catheterization and simultaneous cardiopulmonary exercise test. A six-minute walk distance (6MWD) was determined within 48 hours. MEASUREMENTS AND MAIN RESULTS A resting MPAP above the median (17 mm Hg) was associated with decreased 6MWD (396 +/- 71 vs. 488 +/- 76 m; P < 0.005) and peak Vo(2) (76 +/- 11% vs. 90 +/- 24%; P = 0.05). Resting pulmonary vascular resistance was inversely correlated with 6MWD (r = 0.45; P < 0.05). At 25 and 50W, MPAP above the median (23 and 28 mm Hg) was associated with decreased 6MWD (P < 0.005; P < 0.0005). At peak exercise, MPAP showed no association with 6MWD or peak Vo(2); however, cardiac index was positively (r = 0.45; P < 0.05) and pulmonary vascular resistance was negatively correlated with 6MWD (r = -0.38; P < 0.05). CONCLUSIONS MPAP and resistance in the upper normal range at rest and moderate exercise are associated with decreased exercise capacity and may indicate early pulmonary vasculopathy in patients with systemic sclerosis. Investigations on the prognostic and therapeutic implications of such borderline findings are warranted. Clinical trial registered with http://www.clinicaltrials.gov (NCT00609349).

Calcinosis cutis: Part I. Diagnostic pathway

Calcinosis cutis is characterized by the deposition of insoluble calcium salts in the skin and subcutaneous tissue. The syndrome is separated into five subtypes: dystrophic calcification, metastatic calcification, idiopathic calcification, iatrogenic calcification, and calciphylaxis. Dystrophic calcification appears as a result of local tissue damage with normal calcium and phosphate levels in serum. Metastatic calcification is characterized by an abnormal calcium and/or phosphate metabolism, leading to the precipitation of calcium in cutaneous and subcutaneous tissue. Idiopathic calcification occurs without any underlying tissue damage or metabolic disorder. Skin calcification in iatrogenic calcinosis cutis is a side effect of therapy. Calciphylaxis presents with small vessel calcification mainly affecting blood vessels of the dermis or subcutaneous fat. Disturbances in calcium and phosphate metabolism and hyperparathyroidism can be observed.

Antigenic Conservation of an Immunodominant Invariable Region of the VlsE Lipoprotein among European Pathogenic Genospecies of Borrelia burgdorferi SL

Lyme disease is caused by genetically divergent spirochetes, including 3 pathogenic genospecies: Borrelia burgdorferi sensu stricto, B. garinii, and B. afzelii. Serodiagnosis is complicated by this genetic diversity. A synthetic peptide (C(6)), based on the 26-mer invariable region (IR(6)) of the variable surface antigen of B. burgdorferi (VlsE), was used as ELISA antigen, to test serum samples collected from mice experimentally infected with the 3 genospecies and from European patients with Lyme disease. Regardless of the infecting strains, mice produced a strong antibody response to C(6), which indicates that IR(6) is antigenically conserved among the pathogenic genospecies. Twenty of 23 patients with culture-confirmed erythema migrans had a detectable antibody response to C(6). A sensitivity of 95.2% was achieved, with serum samples collected from patients with well-defined acrodermatitis chronica atrophicans. Fourteen of 20 patients with symptoms of late Lyme disease also had a positive anti-IR(6) ELISA. Thus, it is possible that C(6) may be used to serodiagnose Lyme disease universally.

Calcinosis cutis: part II. Treatment options.

Because calcinosis cutis is a rare syndrome, there is a notable lack of controlled clinical trials on its treatment. The efficacy of calcinosis treatment has only been reported in single cases or small case series. No treatment has been generally accepted as standard therapy, although various treatments have been reported to be beneficial, including warfarin, bisphosphonates, minocycline, ceftriaxone, diltiazem, aluminium hydroxide, probenecid, intralesional corticosteroids, intravenous immunoglobulin, curettage, surgical excision, carbon dioxide laser, and extracorporeal shock wave lithotripsy.

Assessment of Pulmonary Arterial Pressure During Exercise in Collagen Vascular Disease : Echocardiography vs Right-Sided Heart Catheterization

BACKGROUND This study compared the results of exercise Doppler echocardiography (EDE) with right-sided heart catheterization (RHC) and evaluated the combination of EDE and cardiopulmonary exercise testing (CPET) as a screening method for early pulmonary vasculopathy in patients with connective tissue disease. METHODS Patients (N = 52) with connective tissue disease (predominantly systemic sclerosis) and without known pulmonary arterial hypertension underwent both EDE and CPET. If systolic pulmonary arterial pressure (SPAP) was > 40 mm Hg during exercise or peak oxygen uptake (Vo(2)) was < 75% predicted, RHC was suggested. RESULTS EDE showed an SPAP > 40 mm Hg during exercise in 26/52 patients. Additionally, CPET showed a peak Vo(2) < 75% predicted in 10/26 patients with SPAP <or= 40 mm Hg upon exercise. Accordingly, RHC was suggested to 36 patients. RHC was performed in 28 of these patients, revealing SPAP > 40 mm Hg in 25 patients (n = 1 at rest, n = 24 during exercise). SPAP values assessed by EDE showed no significant difference vs RHC at rest, 25 W, 50 W, and maximal exercise (difference [95% CI]: 0.3 [-2.7; 3.2], -1.3 [-7.1; 4.4], 0.9 [-7.7; 5.9], and -5.6 [-13.5; 2.2] mm Hg). Eight patients with exercise SPAP > 40 mm Hg had an exercise pulmonary arterial wedge pressure > 20 mm Hg, suggesting exercise-induced left ventricular diastolic dysfunction not detectable by EDE. CONCLUSIONS EDE appears to be a reasonable noninvasive method to detect SPAP increase during exercise in connective tissue disease. In combination with CPET, it may be a useful screening tool for early pulmonary vasculopathy, although RHC remains the gold standard for hemodynamic assessment. TRIAL REGISTRATION clinicaltrials.gov; Identifier: NCT00609349 (Early Recognition of Pulmonary Arterial Hypertension).

Pulmonary arterial hypertension therapy may be safe and effective in patients with systemic sclerosis and borderline pulmonary artery pressure

OBJECTIVE Borderline pulmonary arterial hypertension (PAH), characterized by a marked exercise-induced increase in pulmonary artery pressure (PAP) with normal resting values, may precede overt PAH in systemic sclerosis (SSc). We undertook the present study to investigate whether PAH treatment is safe in these patients and might attenuate hemodynamic progression. METHODS SSc patients with borderline PAH underwent right heart catheterization at baseline, after a 12-month observation period, and subsequently after 6 months of bosentan therapy. Changes in mean PAP at 50W during the observation period versus during therapy were compared. RESULTS Ten patients completed the study. Mean PAP at rest, at 50W, and during maximal exercise increased significantly during the observation period (mean ± SD increases of 2.5 ± 3.0 mm Hg [P = 0.03], 4.0 ± 2.9 mm Hg [P = 0.002], and 6.8 ± 4.1 mm Hg [P = 0.0005], respectively) and tended to decrease during the treatment period (decreases of 2.5 ± 3.9 mm Hg [P = 0.07], 1.5 ± 4.5 mm Hg [P = 0.32], and 1.8 ± 7.0 mm Hg [P = 0.43], respectively). The changes during the observation period versus the therapy period were significantly different (P = 0.03 at rest, P = 0.01 at 50W [primary end point], and P = 0.02 during maximal exercise). The changes in resting pulmonary vascular resistance were also significantly different during the observation period (increase of 8 ± 25 dynes · seconds · cm(-5) ) versus during the therapy period (decrease of 45 ± 22 dynes · seconds · cm(-5) ) (P < 0.0005). Changes in resting pulmonary arterial wedge pressure were not significantly different between the observation period and the treatment period, despite the significant increase during the observation period (2.6 ± 2.5 mm Hg [P = 0.01]). No relevant adverse effects were reported. CONCLUSION In SSc patients with borderline abnormal pulmonary hemodynamics, resting and exercise PAP may increase significantly within 1 year of observation. Bosentan might be safe and effective to attenuate these changes. Randomized controlled trials are warranted to confirm the exploratory findings of this hypothesis-generating pilot study.

Late-onset Papillon-Lefèvre syndrome without alteration of the cathepsin C gene

Mutations in the cathepsin C gene have recently been detected in Papillon-Lefèvre syndrome (PLS). Until now, 5 cases with the late-onset variation of this disease have been reported in the literature. The genetic background of this type of PLS is still unknown. We describe a 46-year-old woman with late-onset transgredient palmar hyperkeratosis and a 10-year history of severe periodontal disease. Histology of skin biopsy specimens revealed a psoriasiform pattern. Dental examination showed severe gingival inflammation with loss of alveolar bone. Dental plaque investigated by a polymerase chain reaction method revealed DNA signals of 5 different dental bacteria. DNA from EDTA blood was investigated for mutations in the cathepsin C gene by polymerase chain reaction analysis and direct sequencing. A silent variation in the codon for proline-459 was detected but interpreted as a polymorphism of this gene. All genetic linkage and mutation studies for PLS performed so far have shown that PLS is genetically homogeneous. Our patient with late-onset variation of PLS, however, did not show a mutation in the cathepsin C gene. Thus, we suspect that there is another genetic cause for the late-onset forms of PLS.

Schnitzler syndrome: response to anakinra in two cases and a review of the literature.

Background  Schnitzler syndrome is a rare disease characterized by a chronic urticarial eruption and monoclonal gammopathy, as well as clinical and laboratory signs of inflammation. The pathophysiology is still unknown, although various autoantibody‐mediated mechanisms have been described. Complete remission of symptoms has been reported recently in patients with Schnitzler syndrome treated with anakinra, an interleukin‐1 receptor antagonist.

Diagnosis and Therapy of Localized Scleroderma

Localized scleroderma is a rare autoimmune disease with primary affection of the skin, and occasional involvement of the fat tissue, muscle, fascia, and bone. Depending on the clinical subtype, the spectrum of skin lesions ranges from singular plaque lesions to severe generalized or linear subtypes which may lead to movement restrictions and permanent disability. This German S1-guideline proposes a classification of localized scleroderma that, considering the extent and depth of fibrosis, distinguishes limited, generalized, linear, and deep forms of localized scleroderma, together with its associated subtypes. The guideline includes a description of the pathogenesis, of differential diagnoses, and particular aspects of juvenile localized scleroderma, as well as recommendations for histopathologic, serologic, and biometric diagnostic procedures. Based on studies of topical and systemic treatments as well as phototherapy for localized scleroderma published in international literature, a treatment algorithm was developed which takes account of the different subtypes and the extent of disease.Localized scleroderma is a rare autoimmune disease with primary affection of the skin, and occasional involvement of the fat tissue, muscle, fascia, and bone. Depending on the clinical subtype, the spectrum of skin lesions ranges from singular plaque lesions to severe generalized or linear subtypes which may lead to movement restrictions and permanent disability. This German S1‐guideline proposes a classification of localized scleroderma that, considering the extent and depth of fibrosis, distinguishes limited, generalized, linear, and deep forms of localized scleroderma, together with its associated subtypes. The guideline includes a description of the pathogenesis, of differential diagnoses, and particular aspects of juvenile localized scleroderma, as well as recommendations for histopathologic, serologic, and biometric diagnostic procedures. Based on studies of topical and systemic treatments as well as phototherapy for localized scleroderma published in international literature, a treatment algorithm was developed which takes account of the different subtypes and the extent of disease.

Occurrence of subacute cutaneous lupus erythematosus after treatment with fluorouracil and capecitabine

Capecitabine, an oral fluoropyrimidine and 5-fluorouracil (FU) prodrug recently approved for the treatment of metastatic colon and breast cancer, is currently under investigation in patients with gastric cancer. It has the advantage of oral administration, and good tolerability with its activity being comparable with intravenous 5-FU. Lupus erythematosus and lupuslike drug eruptions have been observed after 5-FU treatment, but so far no cases of subacute cutaneous lupus erythematosus have been described in patients treated either with capecitabine or 5-FU. We report a patient who developed subacute cutaneous lupus erythematosus after administration of 5-FU and capecitabine.