Peter A. Miescher

Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Candida albicans liver abscess

Reported here is a case of hereditary myeloperoxidase deficinecy in a diabetic patient suffering from a Candida albicans liver abscess. Peroxidase activity is completely absent from the neutrophils and monocytes although it is present in the eosinophils. The different forms of myeloperoxidase deficiency are discussed.

Drug combination therapy of systemic lupus erythematosus

ConclusionsThis long-term study on 73 patients with severe SLE has shown that drug combination therapy with steroids, CsA, MTX and Cy permits a control of disease activity and maintenance of kidney function with very few side effects and, to a large extent, allows patients a good quality of life in both professional and personal terms. In particular, it has been possible to drastically reduce steroid medication (Table 5). The mortality rate is now well under 1% per year, but is still three to four times higher than in an ageand sex-matched control population. Further efforts are necessary to improve the management of SLE. The investigation of the cytokine network might lead to the introduction of new agents [6]. There is also hope that CsA analogues, devoid of or with less toxicity, will be developed.

Treatment of systemic lupus erythematosus

Over the past 40 years, the methods of evaluation for new drugs have evolved tremendously. Experience based on anecdotal case histories has become almost obsolete with todays objective approach to new drugs or new therapeutic procedures. Controlled studies are open to accurate statistical evaluation which permits an objective assessment of the efficacy as well as the side effects of a new drug or drug combination. For example, much of the progress achieved in the treatment of leukemia is due to this professional approach in the evaluation of new treatment protocols. Initially, experienced hematologists watched this development with suspicion but, as treatment success in leukemia patients increased, the superiority of the new approach was accepted. Gradually, old evaluation methods, including longitudinal individual case observations, were rejected as quite worthless. However, a wave of caution has appeared in recent years. Indeed, a number of valuable drugs such as acetylsalicylic acid would probably not have complied with todays criteria to be admitted for further evaluation. Furthermore, several diseases appear to be unsuitable for evaluation in controlled therapeutic trials, systemic lupus erythematosus (SLE) being a case in particular. For example, it was on the basis of longitudinal observations that clinicians realized that 6-MP without steroids is insufficient for the treatment of SLE patients, yet proves advantageous to the patient, allowing the steroid dose to be decreased. It took more than 10 years of statistically acceptable evaluation to confirm this early clinical conclusion. For many years, scientifically oriented clinicians therefore rejected 6-MP with the justification that its efficacy had not been proven and that, in any case, steroids were more effective. But they forgot to take into consideration the long-term side effects of steroids. In a review on the treatment of SLE, Decker concluded in 1982 [8] that all drugs investigated so far were of questionable ef-

Autoimmune hematologic diseases associated with infraclinical systemic lupus erythematosus in four patients: A human equivalent of the NZB mice

In four patients with a diagnosis of autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura antinuclear antibodies and circulating immune complexes (Clq-BA test) have developed at some time in their history. Renal biopsy material was assayed with different methods. Immunofluorescence studies revealed granular deposits of immunoglobulin G (IgG), immunoglobulin M (IgM) and third component of complement (C3). Upon optic microscopy, three patients had mild mesangial proliferation, one a focal glomerulonephritis. Upon electron microscopy, all patients exhibited mesangial and/or subendothelial deposits. The patients have been followed for 18 to 37 years since the beginning of their disease. There has been no clinical evidence of systemic lupus erythematosus (SLE), although they present in their glomeruli immunologic and anatomic features compatible with this disease. These patients seem to be a human equivalent of the black NZB mouse which presents immunohematologic disorders and some biologic markers of SLE without having a full clinical picture of SLE.

Polyclonal hypergammaglobulinemia in a case of B-cell chronic lymphocytic leukaemia: the result of IL-2 production by the proliferating monoclonal B cells?

Summary. CLL is typically characterized by acquired hypogammaglobulinemia. We report the case of a female patient suffering from B‐CLL who developed polyclonal hypergammaglobulinaemia: 38‐3 g/I polyclonal IgG, 0.97g/1 IgA and 0.33 g/1 IgM. Immunophenotyping showed a monoclonal lymphocytic population CD19+ CD5+ CD40+ CD23+, low slg+ (95%), K type in the great majority (96%). RT‐PCR of immunoglobulin genes gave evidence of monoclonal rearrangement of the IgM type. Our tests showed that IL‐2 was produced when leukaemic B cells were stimulated with phorbol myristate acetate, ionomycin and lipopoly‐saccharide. In addition, transfections with the full IL‐2 promoter or elements thereof revealed that IL‐2 expression is inducible and mediated through the NF‐kB‐promoter element. Finally, the amount of IL‐2 secreted by these cells is about 39ng/ml/106 cells, which is remarkably high for non‐T cells. These results suggest that the large amounts of polyclonal IgG seen in this case of B‐CLL are secreted by normal B cells which are in turn stimulated by IL‐2 produced by proliferating monoclonal (leukaemic) B cells. Under cyclosporin A treatment, immunoglobulin secretion and B cell count remained low.

Prenatal diagnosis of thalassemia and hemoglobinopathies in Switzerland

Abstract:  During a 10‐month period, 10 couples originating from Africa (3), the tropics (1) and the thalassemia‐belt region (6), living in Switzerland, requested prenatal diagnosis of hemoglobinopathies. Hb SS (twice), Hb Barts (Hydrops fetalis) and β‐thalassemia major were diagnosed either by gene mapping or by direct detection of the mutations in DNA amplified by the PCR procedure. Whenever it was possible to obtain fetal blood or tissue, diagnosis was confirmed. In one Vietnamese man, concomitant existence of α‐thal 1 with β‐thalassemia resulted in an unusually high Hb level because of balanced α and β globin synthesis. The 10 couples examined originated from 7 different countries and presented at least 7 different Hb pathologies. This variety of pathologies represents the main difficulty for prenatal diagnosis of hemoglobinopathies in a non‐endemic country. A diagnostic approach to overcome this problem is developed.

Autoimmune disorders: a concept of treatment based on mechanisms of disease

The history of autoimmunity is almost as old as the history of immunology. In 1890 Behring and Kitisato [1], working in Koch’s institute, demonstrated that the serum of animals immunized against attenuated diphtheria toxins can be used as a preventive or therapeutic inoculation against diphtheria in other animals through a specific neutralization of the toxin of the disease. This discovery initiated the long history of the elucidation of the immune response. Just 10 years later Metalnikof [2] challenged the possibility of an immune response against self-constituents of the organism on the basis of his studies on guinea pigs immunized with spermatozoids. A few years later Chauffard and Vincent [3] reported the first case of autoimmune hemolytic anemia (AIHA) and Fiessinger [4] described anti-liver antibodies in patients suffering from chronic active hepatitis (CAH). Nevertheless, in the 1950s the idea of the immune apparatus being used against self-antigens was still considered absurd. The very existence of autoimmune disorders was questioned. Until recently, multiple sclerosis (MS) was considered a viral disease, and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) to be caused by infectious agents, especially of the mycoplasma family. Interest in autoimmune diseases grew slowly but constantly in view of the intensive research being carried out in experimental animals as well the clinical research being carried out on thyroid disorders, RA, SLE, and MS. It is now known that autoimmunity is not a rare event as was thought 50 years ago but is a frequent condition with over 40 recognized autoimmune diseases affecting more than

Drug-combination therapy of rheumatoid arthritis

With the acceptance of the autoimmune pathogenesis of rheumatoid arthritis (RA), resistance to immune suppressive therapy of this disabling disease is gradually disappearing. Like all chronic autoimmune diseases, there is a wide spectrum of disease expression from very mild to very severe forms. Pincus [28] stressed this point by differentiating between patients in the general population with a mild form, usually self limiting, and most patients identified in clinical rheumatology. Patients in the former group are unlikely to have residual disease 3-5 years later, while patients in the latter group will probably have evidence of disease 3-5 years later, generally with progression of the disease process. This paper deals with treatment of the severe, self-perpetuating form of RA. With the increasing evidence of the predominant role of T lymphocytes in the pathogenesis of RA, it seemed logical to try cyclosporine A (CsA) for the control of disease activity in view of its selective immune suppressive action via T lymphocytes. Experience thus far has shown that no currently available drug is capable of controlling disease activity if used as monotherapy. This is certainly the case with CsA. In 1983 we first tried CsA in association with small doses of steroids, given on 4 days per week, in 4 patients. Three of the patients noted a certain improvement, but not sufficient to justify this combination therapy for severe forms of RA [21]. Subsequently, we added weekly injections of methotrexate (MTX), 15 mg i.v. or i.m., for 4 out of 6 weeks. Far better results were obtained with this drug combination [20]. Upon kidney biopsy, no relevant signs of CsA toxicity were found and this drug combination therapy was applied to an additional 25 patients [21]. To assess treatment efficacy, a standard score of clinical and laboratory parameters was used [20]. To assess disease activity in terms of normalisation of lectin-induced IL-2 production as well as spontaneous Ig production in tissue culture, a lymphocyte activity score [14] was used. It was essentially the lymphocyte activity score which implied the need for rather prolonged