Biomedical subjects
Publications and source records attributed to J K Shornick.
Several reported dermatoses of pregnancy have not survived the scrutiny of time and thus including them in current classification schemes does not serve any useful purpose. This review resolves issues in the existing conflicting literature.
Pemphigoid gestationis (PG) is a rare, autoimmune skin disease associated with pregnancy or the immediate post-partum period, previously shown to be associated with the HLA class II antigens DR3 and DR4. Advances in molecular analytical techniques now allow the identification of HLA alleles previously difficult to define by serological assays. Unsuspected polymorphism within the HLA-DR3 and DR4 classes can, therefore, be identified. The aim of our study was to apply these newer techniques to the question of genetic predisposition in PG by re-evaluating the association with DR3 and by studying a possible link with DQ. We have investigated by restriction fragment length polymorphism, the DQA, and by sequence specified oligonucleotide probing the DQB and DRB1 (HLA DR) specificities of 41 women with immunofluorescence-confirmed PG. The principal finding of this study is that there is an association between PG and DRB1*0301 (DR3) and DRB1*0401/040X (DR4). Although there is also an increase (P = 0.06) in the concurrent presence of both antigens, this appears to be due to the association with either antigen alone. We also found an increase in the frequency of DQA1*2 (P = 0.016 vs. control) and a decrease in frequency of DQB1*0201 (P = 0.022 vs. controls) and DQB1*0602 (P = 0.026 vs. controls).
BACKGROUND: Herpes gestationis (HG) is a rare, pregnancy-related skin disease characterized by the production of an autoantibody to a component of the hemidesmosome. It is associated with the class II antigens HLA-DR3 and HLA-DR4, but its potential association with the "class III antigens" C2, C4, and factor B has not previously been studied. OBJECTIVE: Our purpose was to study complement polymorphism in HG. METHODS: Using electrophoresis and immunofixation techniques, we determined the allele frequencies of C4A, C4B, C3, and factor B in 42 patients with a history of HG. RESULTS: Ninety percent of patients carried a C4 null allele (C4*QO). No statistically significant association with C3 or factor B alleles was seen. CONCLUSION: HG is associated with the presence of a C4*QO. Whether the C4*QO is the primary genetic association, or whether the C4*QO is related to its linkage disequilibrium with DR3 and DR4 has yet to be determined.
Pemphigoid gestationis (PG; herpes gestationis) is a rare autoimmune disease associated with pregnancy, currently defined by the presence of complement deposition along the cutaneous basement membrane zone. It is known to be associated with HLA-DR3 and DR4, and an increase in anti-HLA antibodies in those with a history of PG has been reported. We have studied 39 patients with an immunofluorescence-confirmed diagnosis of PG for the presence and specificity of anti-HLA antibodies. Anti-HLA antibodies were found in all 39 patients. Specificity was against class I antigens in 98% (controls 10%; P < 0.001) and class II antigens in 25% (controls 8.5%; P < 0.001). Almost all anti-HLA antibodies were cytotoxic. The universal presence of anti-HLA antibodies in PG suggests that they may develop coincidently with antibasement membrane antibodies, and may reflect a common immunological event.
HG expresses a broader clinical range than previously thought. Disease may be mild and nonvesicular during one pregnancy, followed by explosive vesiculobullous disease during another. On the other hand, patients with extensive HG during one pregnancy may experience mild or even subclinical disease during a subsequent gestation. The broad range of clinical signs and the lack of demonstrable fetal or maternal risk associated with HG have important ramifications for patients desirous of further children. There is a genetic predisposition to HG. DRB1*0301 (HLA-DR3) is increased and 90% of patients express either DRB1*0301 (HLA-DR3) or DRB1*0401/040X (HLA-DR4). Ninety percent of patients also carry a C4 null allele, which may be due to linkage dysequilibrium with DRB1*0301 or DRB1*0401/040X. The disease appears to be mediated by an IgG1 specific for a 180-kD component of hemidesmosomes. This protein is distinct from the 240-kD hemidesmosomal antigen seen in BP and is coded for by a different cDNA on a different chromosome. Abnormal expression of class II MHC occurs in the placental villi of those with HG, suggesting ongoing immunologic stimulation. This has led some investigators to believe that the primary immunologic event is taking place within the placenta and that the skin is an immunologic bystander.
BACKGROUND: The potential risks to the fetus in herpes gestationis have long been a controversial subject, but because of the rarity of the disease, have only occasionally been studied. OBJECTIVE: The purpose of this study was to determine the incidence of fetal complications in herpes gestationis. METHODS: We collected and analyzed the obstetric histories of 74 patients and compared their involved pregnancies with their uninvolved pregnancies. RESULTS: There was an obvious tendency for premature delivery associated with herpes gestations. A slight tendency toward small-for-gestational-age newborns associated with herpes gestationis was confirmed, but, perhaps surprisingly, no increase in spontaneous abortions or stillbirths was noted. The use of systemic steroids did not appear to influence risk. CONCLUSION: Herpes gestationis is associated with an increase in prematurity and small-for-gestational-age infants.
BACKGROUND: Herpes gestationis (HG) is an autoimmune disease of the skin that occurs exclusively in association with pregnancy (or trophoblastic disease). It is associated with the HLA-DR3 and -DR4 antigens that are also associated with several other autoimmune diseases. HG has previously been reported in association with Graves' disease. OBJECTIVE: Our purpose was to determine the frequency of other autoimmune disease(s) in patients with a history of HG. METHODS: Seventy-five patients with a history of HG were studied for the frequency of other autoimmune diseases. RESULTS: We found an increased frequency of Graves' disease in patients with a history of HG. Those with HG have an increased risk for the development of other autoantibodies. There is an increased frequency of autoimmune diseases in the family members of patients with HG. CONCLUSION: Secondary autoimmune disease in HG is unusual, but does occur. The most frequent is Graves' disease.
We describe six patients with cutaneous manifestations of lupus erythematosus who were treated with isotretinoin, 1 mg/kg/day. In each case the cutaneous lesions had proved resistant to systemic corticosteroids and antimalarial therapy. Treatment with isotretinoin resulted in rapid clinical improvement in all cases. Recurrences were similarly rapid when the drug was discontinued. Side effects were minimal and easily controlled by adjustments in dose or by the use of lubricants.
Only 14 years have elapsed since immunofluorescence techniques revised our concept of herpes gestationis. As our inquiry broadens, the answers seem farther away. Yet much knowledge has been gained regarding predisposition and the pathomechanism of this elusive disease. I offer a review of historical context and an update on our current confusions regarding this rare autoimmune dermatosis of pregnancy.
Two middle-aged men presented with generalized erythroderma, diffuse alopecia, and hyperkeratosis of the palms and soles. Histopathologic study demonstrated spongiosis (epidermal intercellular edema) with a perivascular lymphohistiocytic infiltrate. Complete immunologic evaluation demonstrated that both patients had panhypogammaglobulinemia and markedly depressed in vitro pokeweed mitogen-induced immunoglobulin secretion. One of the patients also showed poor lymphocyte responses in vitro to T cell mitogens and antigens and had a decreased ratio of helper to suppressor cells. In both patients, the cutaneous lesions improved with systemic corticosteroids, but no significant alteration in the immunologic abnormalities was observed. This report illustrates that chronic erythroderma may be the presenting clinical manifestation of common variable hypogammaglobulinemia.
To our knowledge, only two cases of herpes gestationis (HG) have been previously reported in black patients. We describe herein two black women with confirmed HG. Both had typical historical and clinical features of the disease. Direct immunofluorescence microscopy demonstrated complement deposition along the dermoepidermal junction in both women. Where HLA typing was possible (in one patient), the combination of HLA-DR3 and HLA-DR4 was found. In addition, anti-HLA-DR2 antibodies were present in serum samples taken from this patient. The occurrence of the HLA-DR3-DR4 combination has been reported to be greatly increased in whites with HG (43%, as compared with a 3% incidence in control subjects). The HLA-DR4 antigen is uncommon in American blacks, which may explain the infrequent occurrence of HG in this population. The occurrence of the DR2 antigen is increased in the husbands of women with HG, and this increase is most pronounced in the husbands of patients with the DR3-DR4 combination. The occurrence of positive immunofluorescence microscopy findings, together with the presence of a rare histocompatibility antigen combination previously associated with HG and the presence of anti-DR2 antibodies in the serum of one of our patients all suggest that HG is pathogenically identical in both blacks and whites.
We have studied 28 patients with well-documented herpes gestationis (HG) to determine the frequency of complications and to review the histopathology, immunopathology, and clinical parameters of disease. The frequency of miscarriages and other maternal complications in our series was not extraordinary. Fetal complications were similarly limited. Less than 5% of infants had cutaneous lesions, and no other untoward fetal complications were apparent. Although the clinical features of our patients largely paralleled those typically reported for patients with HG, several variants of disease were noted. We report one woman with immunofluorescence-confirmed HG who had no clinical disease during a subsequent pregnancy. We also identified cases in which the characteristic vesiculobullous lesions of HG never developed. Instead, four women had urticarial papules or plaques throughout their clinical courses. HG was verified in these four women by typical immunofluorescent findings and by recurrent, classical disease during subsequent pregnancies in two. In addition, two women were identified with recurrent HG during pregnancies by different husbands.
Idiopathic atrophie blanche (segmental hyalinizing vasculitis; livedo reticularis with summer ulceration) is a chronic cutaneous disorder of young to middle-aged women that is characterized by persistent painful leg ulcerations. Primary lesions consist of purpuric macules and papules which undergo superficial ulceration, followed eventually by the development of irregular, atrophic, porcelain white scars with fine borders of ectatic vessels. We have studied twelve patients with idiopathic atrophie blanche by immunofluorescence, thin section light microscopy, and electron microscopy. All patients were examined extensively in order to rule out primary immunologic and vaso-occlusive disorders that may result in a similar clinical appearance. Subsequently, ten patients were treated for 1 to 12 years with combinations of phenformin and ethylestrenol. Each treated patient noted rapid improvement in existing lesions, significantly less pain, and a decrease in the development of new lesions. Side effects in all but two patients were minimal and well tolerated. Light and electron microscopic examination of early and well-developed lesions revealed fibrin plugs which first occlude superficial dermal vessels, followed by necrosis and obliteration of the affected vessel walls. Eventually, new vessel formation occurs in some areas of fibrin deposition. Polymorphonuclear leukocytes and mononuclear cells only rarely participate in this process. Although this disorder has previously been considered a localized form of cutaneous vasculitis, the absence of both leukocytes and nuclear fragmentation from the neighborhood of vascular structures in early lesions differentiates this disorder from immune complex-mediated necrotizing vasculitis. Thus the term vasculopathy describes this disorder more appropriately than the term vasculitis.
It has been suggested that anti-HLA antibodies might be involved in the pathogenesis of herpes gestationis (HG). Accordingly, we have studied the frequency and specificity of such antibodies in 26 female patients with immunologically proven HG. In addition, to further investigate the potential association of the husband's antigens in the development of this disorder, we have performed HLA typing in 20 of the husbands of these women. HLA-DR2 was found in 50% of the husbands (controls 25%, p = 0.04). The increase was more pronounced in the husbands of patients with the HLA-DR3, DR4 combination (64%, p less than .01) than in the husbands of those with other antigen combinations. Anti-HLA antibodies were found in 85% of women with a history of HG. Approximately 25% of normal, multiparous women have such antibodies in their sera. In normal women, their presence has not been associated with increased fetal or maternal risk. These data suggest that the husband's HLA type may be associated with the development of HG in the wife. Anti-HLA antibodies are present in most patients, but their significance remains uncertain.
Herpes gestationis (HG) is a rare, autoimmune, vesiculobullous disease of pregnancy or the puerperium characterized by the deposition of complement (and occasionally immunoglobulin) within the lamina lucida of the cutaneous basement membrane zone. We have studied 23 patients with a history of HG, 20 of whom had typical immunofluorescence findings during the active phase of their disease. HLA typing showed HLA-DR3 in 61% of patients (controls 22%, Pc less than 0.005) and the combination of DR3, DR4 in 43% (controls 3%, Pc less than 0.00001). The most striking finding of this study was that the greatest risk of HG is associated with the concurrent presence of two specific histocompatibility leukocyte antigen (HLA)-DR antigens.