Ingrid Boehm

Management of cutaneous lupus erythematosus with low-dose methotrexate : indication for modulation of inflammatory mechanisms

Abstract There is no consensus about an effective and safe treatment for patients with cutaneous lupus erythematosus (LE) who are refractory to antimalarials and/or low-dose oral glucocorticosteroids. Therefore, we retrospectively analyzed the clinical data and laboratory findings of 12 patients who received weekly administrations of 10–25 mg methotrexate (MTX). Previous treatment with antimalarials and/or glucocorticosteroids was not effective or had to be withdrawn because of side effects. Of 12 patients, ten showed improvement of their skin lesions; two patients did not respond to low-dose MTX; two patients cleared rapidly, and five other patients had long-lasting remissions of 5–24 months after stopping MTX treatment. A reduction of circulating autoantibodies was detected in five patients. In all patients, MTX was well tolerated subjectively and objectively. Weekly low-dose MTX is useful for the treatment of cutaneous LE, particularly in those cases which need long-term treatment and/or do not respond to standard therapeutic regimens.

Antibodies targeting extractable nuclear antigens: historical development and current knowledge

The extractable nuclear antigens (ENA) are a heterogeneous group of ribonucleoproteins and non-histone proteins with different functions in nuclear metabolism. The detection of antibodies targeting ENA is a well-established tool in the diagnosis of autoimmune diseases such as lupus erythematosus (LE), progressive systemic sclerosis (PSS), polymyositis (PM), dermatomyositis (DM), mixed connective tissue disease (MCTD), SjoÈgrens syndrome (SS) and overlap syndromes. Descriptions of precipitin reactions between soluble tissue components and sera of patients suffering from these diseases, as well as identification of the antigen± antibody reactions, have been the subject of a large number of investigations in recent years. Most of the corresponding antigens have been identified (over 20 antigen systems) and knowledge about the clinical and genetic association of the antibodies detected has improved. Antibodies targeting ENA were first described in 1959, when Holman et al. recorded a precipitin reaction of sera from systemic LE (SLE) patients with extractable antigens isolated from crushed calf thymus. This observation was interpreted as an antigen± antibody reaction of autoantibodies in the SLE sera with soluble nuclear antigens. The nomenclature of an autoantibody to ENA depended on the group first describing it, and was made corresponding to the nuclear function of the antigen (RNP), the name of the patient providing the prototype serum (Ro, La, Sm, Jo, Mi) or the disease from which the serum donor suffered (SSA, SSB, SSC, Scl-70, PM-1, PM-Scl). The historical development of antigen±antibody systems lends a depth of understanding to the current knowledge we hold of them. This is particularly true for the systems discussed in this review: Sm, RNP, Ro/SSA, La/SSB, SSC, Scl-70, PM-1, PM-Scl, Ku, Mi and Jo-1. See Table 1 for an overview

Association of inclusion body myositis with subacute cutaneous lupus erythematosus

Abstract. We present the case of a 71-year-old man with inclusion body myositis combined with subacute cutaneous lupus erythematosus and dysphagia. Although inclusion body myositis is usually resistant to immunosuppressive therapy, this patient improved under treatment with corticosteroids. The presented case is discussed in the context of earlier reports of inclusion body myositis and lupus erythematosus.

The value of lymphocytopenia as a marker of systemic involvement in cutaneous lupus erythematosus

Summary Background  Some patients suffering from cutaneous lupus erythematosus (CLE) develop extracutaneous manifestations during the course of the disease: up to 5% of patients with discoid LE (DLE) and up to 30% of subacute cutaneous LE (SCLE) patients show systemic involvement. Recent studies revealed some markers indicating systemic manifestations of CLE patients. However, the significance of diminished peripheral lymphocyte numbers as a marker of systemic involvement in CLE has not been investigated before.

Flame figures in urticarial lesions accompanying systemic lupus erythematosus.

We present the case of a 38-year-old female patient with systemic lupus erythematosus and atypical urticarial skin lesions with an alteration in shape, but not complete disappearance, within 24 hours. Hematoxylin-eosin-stained sections revealed flame figures. We review urticarial lesions in lupus erythematosus and discuss the possible pathomechanisms.

Presence of antinuclear antibodies in patients with lupus erythematosus is correlated with diminished T-helper cells

Sir, Molluscum contagiosum (MC) is a poxvirus skin infection that often complicates the course of patients with acquired or iatrogenic immunosuppression. Both the clinical and histological features of disease in these cases may be atypical. We report the unique clinical and histological features of a case of fulminant MC infection with concomitant leukaemia cutis in a patient with relapse of chronic myeloid leukaemia (CML) after allogeneic bone marrow transplantation (BMT). A 49-year-old Chinese woman underwent BMT (conditioning: busulphan, cyclophosphamide, total body irradiation) from an HLA identical sister for Ph positive CML in accelerated phase. She engrafted uneventfully with no chronic graft-vs.-host disease (GVHD). Serial bone marrow reassessments, up to 18 months post-BMT, were negative for residual disease by polymerase chain reaction and cytogenetics. At 36 months, she was found to have haematological relapse of CML, with cytogenetic subclonal evolution. She was treated with hydroxyurea and donor lymphocyte infusions (DLI) (6 ́1 10 kg cells infused in three doses) to enhance the graft-vs.-leukaemia (GVL) effect. There was good control of the peripheral cell counts and no evidence of GVHD. A repeat marrow biopsy at 40 months showed suppression of the abnormal clone to 3% of analysed metaphases. Unfortunately, at 46 months the disease progressed again with increased neutrophil counts (52 10 L), and leukaemia cutis documented by skin biopsy (Figs 1a, 1b). This was treated with combination chemotherapy (cytosine arabinoside 150 mg 5, thioguanine 160 mg 5) resulting in normalization of cell count and resolution of all skin lesions. A second course of DLI (4 ́2 10 kg cells) was administered at 49 months post-BMT. Three weeks after DLI, however, the patient presented with a dense eruption of erythematous papular lesions over the entire face, upper limbs and upper trunk. Photography of the lesions was refused. A biopsy of one lesion showed lobules of abnormal epidermal cells with cytoplasm packed with eosinophilic viral inclusion bodies (Fig. 2a). Electron microscopy showed numerous intracytoplasmic poxvirus particles (240 95 nm in size) within the abnormal epidermal cells, consistent with MC (Fig. 2b). In addition, an infiltrate of promyelocytes and immature myeloid blast cells was seen, consistent with recurrent leukaemia cutis. She died 1 week later of an intracranial haemorrhage, probably related to intracerebral disease. The use of DLI is the treatment of choice for relapse of CML after BMT. The main side-effects are profound marrow and immune suppression, with or without acute and chronic GVHD. Reactivation of dormant DNA viruses like cytomegalovirus, varicella zoster and hepatitis B viruses are potential complications of immunosuppression caused by DLI. This is the first report of severe MC complicating DLI. In immunosuppressed hosts, due to the fulminant replication of the poxvirus, the clinical and pathological features of MC can be highly variable, and aggressive treatment is often needed. Viral particles have even been found in the histologically normal skin epidermis adjacent to MC lesions in patients infected with HIV. There have been two previous reports of skin changes in MC mimicking haematological malignancy involving the skin. In our case, the clinical setting and pathological features are highly supportive of a genuine double pathology. It is recognized that post-BMT patients have an increased incidence of leukaemic involvement of extramedullary sites, including the skin. The incidence may be even higher in patients salvaged with DLI, due to a weaker GVL effect outside the marrow. The precise colocalization of MC replication and leukaemic infiltration in the skin lesions may have been due to a high concentration of chemotactic

FACS monitoring of lymphocyte-subsets in patients with discoid and subacute-cutaneous lupus erythematosus receiving low-dose methotrexate.

Objective : Our purpose was to describe and characterize the influence of low-dose methotrexate (MTX) treatment on absolute counts of peripheral blood cells and lymphocyte subsets in patients with cutaneous lupus erythematosus (LE). Methods : In 6 patients with discoid (DLE) and 9 patients with subacute-cutaneous LE (SCLE) who received low-dose MTX (10-30 mg/week) leukocytes and lymphocyte subsets were monitored flowcytometrically. Results : Absolute numbers of leukocytes, monocytes, lymphocytes, and lymphocyte subsets displayed cell-type specific patterns under low-dose MTX. Moreover, we found different reaction patterns in patients with DLE and SCLE. In patients with DLE leukocytes, lymphocytes, monocytes (p<0.02), CD3+ cells (p<0.04), CD3+ CD4+ cells (p<0.009), and CD3+ CD8+ cells increase, and only B-cells decrease. Whereas in patients with SCLE no significant changes were found. Conclusion : Low-dose MTX treatment seems to independently influence peripheral blood cell compartments and thereby the underlying LE manifestation could be of some relevance.

Drug treatment-induced downregulation of antiphospholipid antibodies in PAPS

Although low-dose methotrexate (MTX) has been used to treat several autoimmune diseases like lupus erythematosus, rheumatoid arthritis, etc., it has not yet been used to treat patients with primary antiphospholipid syndrome (PAPS). Parallel to clinical follow-up of female patient with a severe form of PAPS, antiphospholipid antibodies (aPL), blood coagulation, and hematological parameters in the peripheral blood have been monitored. MTX improved ulcers, livedo reticularis, decreased aPL titers, increased platelet counts, and improved blood coagulation parameters (e.g., factor VIII) and was well tolerated. Low-dose MTX was safe and effective in the presented case with PAPS. The clinical benefit may be due to the downregulation of increased aPL titers and amelioration of disturbed coagulation parameters.

Wasp-sting-triggered LE

Keywords: apoptosis; isomorphic reaction; Kobners phenomenon; subacute cutaneous lupus erythematosus; wasp sting

Nephrogenic systemic fibrosis in patients undergoing hemodialysis: Comment on the article by Todd et al

To the Editor: I read with great interest the article by Todd and colleagues on the prevalence of nephrogenic systemic fibrosis (NSF) and associated risk factors (1). I would like to congratulate the authors on their work and to make some comments about the study. Previous research on this subject has shown that cutaneous changes in NSF may include edematous swelling and redness, a peau d’orange appearance, slightly raised erythematous or brawny nodular plaques, linear striations, or confluent regions of fibrosis (2–4). Symptoms include burning pain, pruritus, paresthesia, and weakness. Therefore, the 3 criteria used by Todd et al, namely, pigmentation, hardening, and tethering (1), are not sufficiently reliable for characterizing the cutaneous manifestations of NSF. Moreover, as indicated in their Patients and Methods section, examination was limited to the patients’ extremities. With this focus, some patients with primary abdominal fibrosis (5) in the subgroup of patients with “negative” examination results could have been overlooked. Therefore, I do not believe this study provides real insight into the prevalence of NSF in patients undergoing hemodialysis, as is suggested by the authors. Furthermore, since the natural course of cutaneous changes in patients with NSF is largely unknown, no conclusion can be drawn from the number of days from the time of skin examination until the time of death. According to Table 2 of Todd and colleagues’ article, joint contractures were found in 9 patients, and the legend of Figure 1 states that in the patient depicted, “the joints were severely contracted.” Unfortunately, however, joint contracture cannot be seen in the figure. It is notable that the prevalence of NSF was found to be 30%, which is much higher than the percentage reported in the prior literature (2,6). Does this mean that only 54 patients received gadolinium-containing contrast material while the remaining 162 patients did not? Results of magnetic resonance imaging examinations performed on the patients are not presented in Todd et al’s report as they are in other reports (2,6). Furthermore, neither data on the single dose of gadolinium-containing contrast material nor data on cumulative doses are provided in their report, which, according to recently published studies (2,6), makes it difficult to interpret apparent associations. However, Todd and colleagues conclude that, based on their results, exposure to gadoliniumcontaining contrast material appears to be a significant risk factor for the development of NSF, as has been reported previously by other authors (2,6). Our understanding of NSF would be enhanced with additional clinical data from larger patient groups. It would be interesting and helpful if the data could be further supplemented with information on possible additional risk factors, early signs, and evolution of cutaneous changes in NSF.