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Objective: To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism., Methods: Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases., Results: In 2 of the RA patients, the RA remained in remission without treatment, with nonprogressive disease, 11 and 13 years after BMT. The third patient with RA had a relapse 2 years after BMT, although the previously aggressive disease subsequently ran an attenuated course with treatment-free remission for the last 11 years. Comparison with other cases of RA suggests that graft-versus-host disease may influence the long-term outcome, perhaps through ongoing inhibition of the immune system. In the patient with psoriasis, BMT was followed by remission, but the psoriatic rash recurred and arthropathy developed 12 months later. The psoriasis and arthropathy remained active 4.5 years post-BMT, although the CML remained in remission. Molecular studies in the 2 patients whose RA remained in continued remission and in the patient with psoriasis that relapsed confirmed complete donor hemopoietic reconstitution., Conclusion: Long-term followup of autoimmune disease after allogeneic transplantation confirmed cure of the autoimmune disease in some, but eventual relapse in others. The occurrence of relapse despite complete donor hemopoietic reconstitution is evidence for the development of de novo, as opposed to persistent, disease, and is possibly related to intrinsic susceptibility of the transplanted stem cells or to host factors. There may be a relationship between remission of autoimmune disease and graft-versus-host reaction. These findings have relevance for the evolving application of stem cell transplantation as a therapy for autoimmune diseases.

Based on successful results in animal models, it has been proposed that high-dose myeloablative therapy followed by autologous bone marrow or stem cell transplantation (ABMT/ASCT) may cure autoimmune disease. The coexistence of autoimmune disease and hematologic malignancy provides an opportunity to examine the response of autoimmune disease to ABMT or ASCT. We describe 4 patients with autoimmune disease (3 with psoriasis and 1 with rheumatoid arthritis) and hematologic malignancy. In each patient, the autoimmune disease remitted posttransplantation, but, in 4 patients with long-term followup, it recurred at 8-24 months. The earliest relapse occurred in a patient treated with interferon-alpha. Our experience suggests that a single autograft with unpurged stem cells is unlikely to cure autoimmune disease, but that other strategies building on this approach are worthy of investigation.

We report a patient who underwent allogeneic bone marrow transplantation from a sibling with longstanding untreated severe active rheumatoid arthritis. After 4 years of follow-up there is no evidence of adoptive transfer of rheumatoid arthritis to the recipient. This case, along with another recently reported case, provides reassurance that haemopoietic stem cell transplantation from a donor with systemic autoimmune disease may not necessarily result in adoptive transfer of the disease. All previous reports of transfer of autoimmunity in humans have been of organ-specific autoimmune diseases and we speculate that pathophysiological differences might account for why systemic autoimmune disease is not transferred.

Transfer of donor immunity has been demonstrated in animal models of both allogeneic and syngeneic bone marrow transplantation (BMT). Clinical case reports have suggested that human autoimmune disease may be similarly transferred. However, it is difficult to completely exclude autoimmune phenomena associated with graft-versus-host disease (GVHD) as previously reported cases are of allogeneic BMT. In addition, the onset of autoimmunity has been distantly related to the timing of the transplant, perhaps because of the immunosuppression used for prophylaxis and treatment of GVHD. We describe a patient in whom the development of psoriasis shortly after receiving syngeneic bone marrow from a psoriatic donor and its recurrence with arthropathy following a second syngeneic BMT provide more direct evidence for the adoptive transfer of human autoimmune disease, probably by T cells.

The prognostic significance of cytogenetic abnormalities was determined in 106 patients with well-characterized idiopathic myelofibrosis who were successfully karyotyped at diagnosis. 35% of the cases exhibited a clonal abnormality (37/106), whereas 65% (69/106) had a normal karyotype. Three characteristic defects, namely del(13q) (nine cases), del(20q) (eight cases) and partial trisomy 1q (seven cases), were present in 64.8% (24/37) of patients with clonal abnormalities. Kaplan-Meier plots and log rank analysis demonstrated an abnormal karyotype to be an adverse prognostic variable (P<0.001). Of the eight additional clinical and haematological parameters recorded at diagnosis, age (P<0.01), anaemia (haemoglobin < or = 10 g/dl: P<0.001), platelet (< or = 100 x 10(9)/l, P<0.0001) and leucocyte count (> 10.3 x 10(9)/l; P=0.06) were also associated with a shorter survival. In contrast, sex, spleen and liver size, and percentage blast cells were not found to be significant. Multivariate analysis, using Cox's regression, revealed karyotype, haemoglobin concentration, platelet and leucocyte counts to retain their unfavourable prognostic significance. A simple and useful schema for predicting survival in idiopathic myelofibrosis has been produced by combining age, haemoglobin concentration and karyotype with median survival times varying from 180 months (good-risk group) to 16 months (poor-risk group).

We describe a patient with longstanding steroid-dependent systemic lupus erythematosus (SLE) in whom clinical and serological remission was achieved following high-dose therapy and autologous bone marrow rescue for high-grade non-Hodgkin's lymphoma. However, 3 years later, autoimmune disease re-presented in the form of immune thrombocytopenia (ITP), which had not previously been a feature of the SLE, necessitating reintroduction of steroid immunosuppression. Relapse of SLE is most likely, although de novo ITP post-BMT is also a possibility. The case suggests that severe long-standing autoimmune disease may be controlled by high-dose therapy and autologous stem cell reconstitution. However, further studies are required to determine the mechanism of re-emergence of autoimmunity and to evaluate optimal regimens and the potential value of such therapy in severe autoimmune diseases.

We have characterized the first case of Rhnull phenotype to be identified in England. The red cells were serologically negative for C, c, Cw, D, E, e, f, hr B, Rh17, Lw a, Lw ab and Duclos, while the patient's serum contained anti-Rh29, which was subsequently boosted by transfusion. The Rh phenotype of the patient's son (R1r) confirmed that this was a regulator type of Rhnull in the patient. Follow up studies confirmed the presence of a mild chronic anaemia with stomatocytes and spherocytes; electron microscopy revealed the presence of cells with deep central indentations. Osmotic fragility was increased to a level intermediate between normal and hereditary spherocytic controls. The presence of ongoing haemolysis was indicated by a mild reticulocytosis and splenomegaly. The potent anti-Rh29 has made the provision of compatible blood difficult and autologous units have been frozen. The case illustrates the rare phenomenon of the Rhnull phenotype which not only causes problems for the transfusionist but should also be recognized as a cause of haemolytic anaemia secondary to a membrane defect. Blood film and Rh phenotyping are useful preliminary investigations in suspected cases.

We here present the case of a 70-year-old woman referred to our unit for investigation of bleeding. Investigations confirmed a high titre acquired Factor VIII inhibitor. In association there was relapse of systemic illness associated with anti-neutrophil cytoplasmic antibodies (atypical pattern) for which she had been treated five years previously. Immunosuppression was attempted, but it failed to have an impact both on the inhibitor titre and on the underlying disorder. The patient died from multi-organ failure and massive chest hemorrhage. Post-mortem showed necrotizing vasculitis of medium sized vessels at several sites, including the kidney, consistent with a diagnosis of polyarteritis nodosa. Although it is well recognised that Factor VIII inhibitors are found in conjunction with autoimmune disorders, this case is significant in that it is the first associated with histologically proven polyarteritis nodosa type vasculitis. The case illustrates the difficulties in the investigation and management of patients with acquired high titre Factor VIII inhibitors.

Angiotropic lymphoma, also known as intravascular lymphomatosis, is characterised by widespread intravascular proliferation of malignant lymphoid cells, usually without evidence of focal disease. A case of a 52 year old man referred for investigation of a two year history of pyrexia of unknown origin, skin rash and multiple organ failure is described. Angiotropic lymphoma was seen in gastric, colonic and skin biopsy specimens, and review of an earlier skin biopsy specimen showed similar morphological features. In contrast to previous cases which showed B or T cell differentiation, immunohistochemical examination was positive for histiocyte markers. Molecular studies showed no evidence of immunoglobulin heavy chain gene or T cell receptor gene rearrangement. The patient responded to combination chemotherapy, comprising cyclophosphamide, doxorubicin, etoposide, and prednisolone. This case highlights the fact that advanced lymphoma may be present without evidence of focal disease and that the diagnosis may be missed easily both clinically and histologically.

Microvascular occlusion is known to be a feature of myeloproliferative diseases. Acute manifestations are well documented in individuals causing a variety of symptoms. However, it is not known whether ongoing microvascular changes are present in asymptomatic individuals. We investigated this further by using retinal intravenous fluorescein angiography to image the microvasculature in patients with myeloproliferative disease. In our group of patients fluorescein angiography did not show any ongoing microvascular damage. There appears to be no intrinsic retinal vasculopathy in patients with myeloproliferative disease, suggesting that acute symptomatic events are caused by microemboli in an otherwise normal vascular tree.

We report the occurrence of livedo reticularis in a patient with symptomatic hereditary type 1 protein C deficiency. Antithrombin III deficiency and the antiphospholipid syndrome may also be associated with livedo reticularis, and we suggest that a thrombophilia screen may be a useful investigation in a patient with otherwise unexplained livedo, particularly if there is a personal or family history of thromboembolism.

We report the case of a 35 year old female who presented with an 8 year history of repeated upper respiratory tract infection, lymphadenopathy and sinusitis associated with IgG3 deficiency. Courses of monthly intravenous immunoglobulin therapy (0.4 g/kg) resulted in a dramatic clinical improvement on three different occasions. We suggest that investigation of adults with features of immunosuppression, despite normal levels of total IgG, should include IgG3 subclass analysis and that symptomatic patients should be given a trial of immunoglobulin replacement therapy.

A 43 year old woman in remission from acute myeloid leukaemia developed abdominal pain, severe melaena, diarrhoea and gram-negative septicaemia whilst severely pancytopenic following consolidation chemotherapy. Subsequently, serial abdominal X-rays showed a progressive toxic megacolon. Conservative management was attempted but, because of radiological evidence of increasing colonic dilatation and incipient perforation, an emergency defunctioning colostomy was performed. The patient recovered and 2 months later the caecostomy was reversed and a right hemicolectomy performed. This first described case of toxic megacolon following leukaemia treatment is compared with three previously described cases following cytotoxic chemotherapy for other conditions.

We report the sudden and dramatic reversal of maturity onset diabetes in a 57-year-old woman in association with relapse of IgA myeloma diagnosed 3 years earlier. Prior to the relapse of the myeloma, twice daily insulin had been administered at a dose which had been stable for 3 years. However, the same dose produced hypoglycaemic coma at the time of relapse and, subsequently, blood glucose was controlled by diet alone. There had been no significant change in weight or renal function prior to the hypoglycaemic episode. Investigations showed a suppressed fasting serum insulin level in association with an inappropriately high serum level of IGF-II compared with IGF-I and a 'big' IGF-II concentration at the upper end of the normal range. Pituitary, adrenal and liver disease, as well as the autoimmune insulin syndrome, were excluded. The findings are consistent with the hypothesis that the plasma cell tumour was associated with excessive production of insulin-like peptides with consequent reduction in the blood glucose level.

Colonic dilatation has been reported as an occasional complication of infectious colitis in single case reports and short series, but no large series has been published. We analysed 19 cases of self-limited colitis complicated by colonic dilatation, with infective agents identified in 14, admitted to a Regional Infectious Diseases Unit. Colonic dilatation, defined as a minimum transverse colonic diameter of 7 cm on plain abdominal X-ray, was associated with approximately 1% of cases of notifiable diarrhoea requiring hospital admission. The clinical course was associated with pyrexia (in 90%), tachycardia (in 90%), hypoalbuminaemia (in 100%), anaemia (in 84%) and reactive thrombocytosis (in 63%). There was a history of antidiarrhoeal agents or opiate analgesia in eighteen patients (95%). Intensive medical management, consisting of intravenous antibiotics, steroids, supplementary nutrition and withdrawal of anti-motility agents, resulted in resolution in 17 patients. Two patients required subtotal colectomy for perforation of the transverse colon, but neither developed severe peritonitis, and both subsequently underwent reversal of ileostomy. With early recognition and close observation of colonic dilatation in patients with acute diarrhoea, most cases can be successfully managed conservatively with preservation of the colon. Surgical intervention should be considered in patients with progressive colonic dilatation despite intensive medical management. There were no clinically useful parameters distinguishing self-limited colitis from inflammatory bowel disease acutely, so initial management should cover both possibilities.

We report the case of an otherwise healthy young adult woman who has suffered three episodes of lymphocytic meningitis of possible enteroviral aetiology during a 5 year period. Analysis of immunoglobulin subclasses has revealed a sustained reduction of IgG3 to below the fifth percentile. In addition, the patient's father and brother have a similar degree of IgG3 deficiency. Isolated IgG3 deficiency has previously been described in association with recurrent upper respiratory tract infections, asthma, obstructive lung disease and enteral infections. However, our patient did not have any of these and there was no other identifiable immune defect to account for the recurrent meningitis. Although a mere chance association is possible, the case is interesting as antibody responses involving IgG3 tend to be triggered by protein antigens such as viral envelopes, while humoral immunity is known to be important in the clearance of enteroviral infection.

To investigate the hypothesis that aberrant HLA and adhesion molecule expression in alopecia areata (AA) are secondary to local release of interferon-gamma (IFN-gamma) or other cytokines, we have studied HLA ABC, -DQ, -DR and ICAM-1 expression by immunohistochemistry, and compared patterns of expression in lesional tissue sections with those observed in hair follicles maintained in short-term organ culture, both from normal individuals and non-lesional sites in AA patients. The organ cultures were supplemented with IFN-gamma, tumour necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF), in a range of doses. In lesional AA tissue sections, there was close spatial correlation of ICAM-1 with HLA-DR; prominent staining being noted in the pre-cortical matrix and dermal papilla (DP) of lesional anagen follicles. In cultured follicles, dose-dependent induction of HLA class I, DR and ICAM-1 by IFN-gamma, and HLA class I and ICAM-1, but not HLA-DR, by TNF-alpha was observed in follicular epithelium, mainly in the outer root sheath (ORS). The findings in these cultures were the same in follicles derived from normal individuals and AA patients. Cytokine-induced patterns of HLA and ICAM-1 expression observed in vitro in cultured follicles differed significantly from those observed in vivo in lesional tissue sections. In particular, IFN-gamma failed to induce HLA-DR expression in the pre-cortical matrix and dermal papilla (DP), sites where this is usually observed in AA. The results suggest local cytokine release is not the sole determinant of aberrant HLA-DR expression in AA.

Ovarian stromal hyperplasia is commonly observed in peri- and post-menopausal ovaries. Assessment has, hitherto, been largely subjective or dependent on arbitrary criteria, which has made comparison of studies difficult. In this study, the stroma of a large number of ovaries was assessed morphometrically. Data were related to clinicopathological and cytomorphological information. A significant association was noted between the degree of stromal proliferation and post-menopausal endometrial adenocarcinoma (P = 0.004). There were no significant correlations between the degree of stromal proliferation and average cytomorphological dimensions.

Proliferation of ovarian stromal cells is a common phenomenon in peri- and post-menopausal ovaries. It is generally assumed to be secondary to the rise in circulating gonadotrophins at the menopause, though the process by which it occurs is poorly understood. This study aimed to examine the effect of menopausal levels of pituitary gonadotrophins on the growth of primary cultures of ovarian stroma. A culture system was developed using primary explants of ovarian stroma on a collagen substrate. The effect of follicle stimulating hormone (FSH; 10(-5) g/l) and luteinizing hormone (LH; 10(-5) g/l) on the proliferation of cultures derived from the cortices and medullae of ten ovaries was evaluated using a dual radiothymidine labelling technique. FSH was stimulatory to cortical cultures from 9/10 ovaries and medullary cultures from 7/10 ovaries, while LH was stimulatory to cortical cultures from 6/9 ovaries and medullary cultures from 5/10 ovaries. The responsiveness of the cultures did not correlate with the degree of hyperplasia in vivo. This study demonstrates that pituitary gonadotrophins may modulate the growth of stromal cells in culture, and thus may play a role in the process whereby stromal proliferation occurs in peri- and post-menopausal ovaries.