Systemic lupus erythematosus. Studies of the antibodies bound to skin.

Systemic lupus erythematosus is characterized by antibodies demonstrable by immunofluorescence on the renal glomeruli and at the basement membrane area of both normal and involved skin. Acid eluates from glomeruli and from normal-appearing skin of three patients with systemic lupus erythematosus contained an antinuclear antibody. This antibody fixes complement and produces a mixed immunofluorescent pattern. Anti-deoxyribonucleic acid or antiextractable nuclear antigen antibodies may be present. This antibody is concentrated on the skin and glomerular basement membrane in proportion to the total serum IgG concentration. In two cases the skin eluate contains, in addition to the antinuclear antibody, a basement membrane antibody that fixes complement, gives a linear immunofluorescent pattern, and appears to be similar (although not identical) to the pemphigoid antibody.

The complement system in bullous pemphigoid. I. Complement and component levels in sera and blister fluids.

Compared with other serum and blister fluid proteins, total hemolytic complement was reduced in the blister fluid of six serologically positive bullous pemphigold patients while four serologically negative cases had blister fluid complement levels closely approaching the serum levels. Except for pemphigus vulgaris blisters. blister fluids from most patients with other bullous diseases and experimentally induced blisters had blister fluid complement levels more closely approaching the serum levels. With the exception of the two terminal components. C8 and C9, individual components of the complement sequence were also reduced in the blister fluids of the six bullous pemphigold patients with circulating basement membrane zone antibodies. On the other hand, transferrin and IgG levels of these same six serologically positive blister fluids closely approached the corresponding serum levels. Conversion of C3 proactivator was also demonstrable in the serologically positive bullous pemphigoid blister fluids, but not in the corresponding sera. Our studies, therefore, are suggestive of local activation of the complement sequence, by both the classical and alternate pathways, in blisters of serologically positive bullous pemphigold patients.

Hypersensitivity angiitis.

Hypersensitivity angiitis is a disease in which patients present with palpable purpura dominant on the lower legs. As lesions evolve they become confluent, and sometimes hemorrhagic and ulcerate. Other organ systems may be involved, particularly the joints, gastrointestinal tract, and kidneys. Current evidence supports an immune complex pathogenesis in which a variety of antigens including bacteria, viruses, drugs, or chemicals are involved. Therapy consists of identifying the potential offending agent and administration of antiinflammatory drugs.

Human hypersensitivity angiitis, an immune complex disease.

Human hypersensitivity angiitis is an immune complex disease in which patients present with palpable purpuric lesions of the skin and may often have multiple organ involvement. The antigen may be derived from an infectious organism such as the hepatitis virus, streptococcus, or a drug, and complexes with antibody. Under circumstances of vascular turbulence or vessel wall dilatation this complex may become fixed, activating the complement sequence with elaboration of chemotactic factors for neutrophils. These cells release lysosomal enzymes resulting in vessel wall destruction. Red blood cells leak into the tissue producing purpura and the inflammatory infiltrate accounts for the palpability. Although many patients have skin lesions only, others may have involvement of joints, gastrointestinal tract, kidneys, and even the lungs. The central question in the pathogenesis of this disease is why the immune complex is so selective in its site of deposition. Part of the reason must be related to the lattice formation of a particular complex, while other reasons are related to host factors of altered vascular permeability, integrity of clearance mechanisms or even a genetically determined defect of the phagocytic system.

Demonstration of the complement regulating protein, beta 1H, in skin biopsies from patients with bullous pemphigoid.

beta 1H-globulin is a recently characterized plasma protein which regulates the biologic activities of the major fragment of the third complement component, C3b. The major function of this protein is to act as a co-factor for C3b Inactivator (C3bINA) in the cleavage of C3b to an intermediate molecule, C3b', consisting of an intact beta-chain covalently bound by disulfide bridges to 2 alpha-chain fragments of 40,000 and 67,000 daltons. Final cleavage of C3b' to the C3c and C3d fragments requires an additional protease such as plasmin or elastase. Additionally, beta 1H interferes with the activity of the alternative pathway convertases, C3bBb and C3bBbP, by displacing or competing with the binding of factor B. In this study, perilesional skin biopsies from 10 patients with active bullous pemphigoid were examined for the presence of beta 1H at the dermal-epidermal junction by immunofluorescent methods. The protein was found in 8 of 9 biopsies in which C3 also was deposited. In a single case where C3 was not found, beta 1H was not seen. These findings suggest that beta 1H plays a role in the in vivo control of C3b and provides additional evidence for the participation of the complement system in the pathogenesis of bullous pemphigoid.

Pemphigoid antibody mediated attachment of peripheral blood leukocytes at the dermal-epidermal junction of human skin.

It has been proposed that cutaneous inflammation and blister formation in bullous pemphigoid is caused by antibodies to the cutaneous basement membrane zone which active complement, thereby, attracting leukocytes to the dermal-epidermal junction. There is, however, no functional evidence which supports a role for pemphigoid antibodies in complement activation or leukocyte activity in skin. This study describes the in vitro attachment of human peripheral blood leukocytes to the dermal-epidermal junction of cryostat skin sections treated with 9/13 pemphigoid sera containing antibodies to the cutaneous basement membrane zone. A requirement for complement in the reaction was supported by the findings that only complement-fixing pemphigoid sera mediated the leukocyte response, a strong correlation existed between complement-fixation titers and leukocyte attachment titers and only leukocytes suspended in fresh serum but not buffer or heat inactivated serum attached at the junction. A requirement for antibody was supported by the observation that IgG fractions of 4 pemphigoid sera were as effective as whole sera in mediating leukocyte attachment. The leukocyte response was shown to be specific for complement-fixing pemphigoid sera since it was not observed with noncomplement-fixing sera or sera from 15 normal human and 22 nonpemphigoid disease controls. This study offers functional evidence for an interaction between pemphigoid antibody, complement and leukocytes in the immunopathogenesis of bullous pemphigoid and demonstrates that complement-fixing antibasement membrane zone antibodies may be important in initiating the cellular inflammatory events observed near the dermal-epidermal junction in vivo.

Leukocytoclastic vasculitis: sequential appearance of immunoreactants and cellular changes in serial biopsies.

To study the mechanisms responsible for leukocytoclastic vasculitis, we evaluated the kinetics of immunologic and cellular changes in induced vasculitis lesions. In four of five consecutive patients with active vasculitis, lesions were induced by increasing vascular permeability via injecting histamine into the skin. Biopsies were obtained for light and electron microscopy and immunofluorescence at 1, 4, 8, and 24 hr after injection. The results show that immunoglobulin, C3, and electron-dense material are deposited in vessel walls early and are followed by cellular infiltration. The characteristics of the cellular infiltrates were quite diverse at different times after histamine provocation and no distinctive patterns were seen. Nevertheless, the kinetics of the appearance of immunoreactants and cells implies that immunoglobulin and probably circulating immune complexes are present prior to the development of inflammation and supports the contention that deposition of immune complexes within vessel walls is responsible for leukocytoclastic vasculitis.

Human necrotizing vasculitis: immunoglobulins and complement in vessel walls of cutaneous lesions and normal skin.

Immunoglobulins and C3 were detected by immunofluorescence in the blood vessel walls of biopsies of clinically normal skin in patients with active necrotizing vasculitis. Of the 13 patients studied, 9 had C3 and 6 of these had IgM or IgA in biopsies of lesions of vasculitis. In adjacent clinically normal skin, 7 patients had C3 and 3 of these also had IgM or IgA. These findings support the hypothesis that immunoglobulins and complement are present in vessels of some patients prior to chemotaxis of polymorphonuclear leukocytes and the resulting inflammatory purpuric lesions so characteristic of necrotizing vasculitis.

Functional evidence for complement-activating immune complexes in the skin of patients with bullous pemphigoid.

Previous immunofluorescent studies showing deposits of immunoglobulin and complement at the cutaneous basement membrane zone have provided evidence supporting a role for immune complexes in the pathogenesis of bullous pemphigoid. In this study the functional activity of the deposits has been examined using leukocyte attachment, a method for detecting and quantitating the biological activity of complement-activating immune complexes in tissues. When peripheral blood leukocytes suspended in serum complement were incubated with cryostat sections of lesional and adjacent normal-appearing skin from 9 patients with pemphigoid, skin from 11 normal controls and lesional skin from 14 nonpemphigoid disease controls there was significantly greater attachment of leukocytes to the basement membrane zone of lesional bullous pemphigoid skin compared to normal-appearing pemphigoid skin and skin of both control groups. A significant reduction in attachment in the absence of serum complement suggested the reaction was dependent on activation of complement by tissue-deposited complexes. Although leukocyte attachment was greater in lesional than normal-appearing pemphigoid skin, a comparison of the incidence and intensity of cutaneous IgG and complement immunofluorescence between the 2 groups showed no significant differences. Furthermore, no correlation between leukocyte attachment and serum titers of immunoglobulin G or complement-binding anti-basement membrane zone antibodies was observed. These results suggest that immune reactants in lesional pemphigoid skin are functional complement-activating immune complexes, that differences exist between the activity of complexes in lesional and normal-appearing pemphigoid skin and may explain why lesions develop at some sites and not others.

An in vitro model of immune complex-mediated basement membrane zone separation caused by pemphigoid antibodies, leukocytes, and complement.

In this study, an in vitro model of immune complex-mediated basement membrane zone separation caused by periphigoid antibodies, serum complement, and peripheral blood leukocytes is described. When cryostat sections of fresh-frozen normal human skin were treated with either of 4 bullous pemiphigoid sera containing complement-activating anti-basement membrane zone antibodies and subsequently incubated at 37 degrees C with normal human peripheral blood leukocytes and fresh human serum, leukocytes attached to 96% of the basement membrane zone in 100% of sections. Sixty-seven percent of the sections developed focal areas of basement membrane zone separation resembling dermal-epidermal separation described in early pemphigoid lesions. In control sections in which either leukocytes, pemphigoid antibody or fresh human serum were omitted, significantly less leukocyte attachment and basement membrane zone separation occurred. Evidence that leukocytes caused separation was supported by an absolute requirement for viable leukocytes during incubation, a high correlation between leukocyte attachment and separation and experiments showing that leukocytes attached to the basement membrane zone were activated. This study provides the first in vitro evidence directly supporting a functional role for immune-complex mediated inflammation in the pathogenesis of basement membrane zone separation and blisters in bullous pemphigoid.

Chronic mucocutaneous candidiasis. Immunologic studies of three generations of a single family.

A family consisting of eight members in three generations (age 10 months to 53 years) affected with chronic mucocutaneous candidiasis was studied along with three unaffected relatives. Dermatophytosis, loss of teeth and recurrent viral infections were present in some members. Results of tests for endocrinologic, muscle or liver disease, thymoma, iron deficiency, antitissue antibodies and malabsorption were normal in all patients. Antibody function and levels, B cell counts, serum complement, leukocyte enzymes, chemotaxis, phagocytosis and adherence were normal in all members. Plasma inhibitors to lymphocyte transformation and leukocyte inhibitory factor were not found. No unique HLA haplotype or antigen segregated in this family. Evaluation of cell-mediated immunity revealed total cutaneous anergy in three of eight whereas four of the other five had negative lymphocyte transformation and skin tests to Candida but responded normally to other antigens. Leukocyte inhibitory factor was not produced to Candida antigen in all four patients tested. T cell counts were within normal limits in all. Extensive evaluation of all limbs of the immune system in this family revealed a defect in cell-mediated immunity to Candida that appeared to be inherited as a dominant characteristic.

Morning plasma cortisol levels in infants treated with topical fluorinated glucocorticosteroids.

The plasma cortisol levels of 17 infants of mean age 12.1 months taken at 8 AM were measured before and after application of a topical fluorinated glucocorticosteroid. There was a statistically significant depression of plasma cortisol value in 11 infants at days 3, 7, and 14 after therapy. All of the plasma cortisol levels returned to normal. For the entire group of 17 infants, however, there was no significant depression of plasma cortisol levels. Even in the usual office use of topical glucocorticosteroids, one must be aware of the possiblity of percutaneous absorption.

Hyperandrogenemia in patients presenting with acne.

OBJECTIVE: To determine whether acne is associated with hyperandrogenemia, regardless of age of presentation. DESIGN: Prospective controlled study. SETTING: Tertiary-care medical center. PATIENT(S): Thirty consecutive unselected women presenting with acne and no hirsutism and 24 eumenorrheic healthy controls. INTERVENTION(S): Serum samples was taken in all patients, and an acute 60-minute ACTH-(1-24) test was performed in 19 patients. MAIN OUTCOME MEASURE(S): Total and free T, sex hormone-binding globulin (SHBG), and DHEAS levels in basal samples, and ACTH-stimulated 17-hydroxyprogesterone (17-HP) response to exclude 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) were determined. RESULT(S): Nonhirsute patients with acne demonstrated significantly lower levels of SHBG and higher free-T and DHEAS levels than controls. Nineteen (63%) acneic patients had at least one androgen value above the 95% of controls. In patients aged 12-18 years, 7/8 (88%) had at least one increased androgen value, compared with 12/22 (55%) patients aged 19-43 years. One patient (5.3%) was found to have 21-OH-deficient NCAH. CONCLUSION(S): Hyperandrogenemia was evident in a majority of nonhirsute acneic patients studied, regardless of age. These data suggest that androgen suppression may be useful in treating acne in many of these patients.

Livedo vasculitis. Therapy with pentoxifylline.

Eight patients with livedo vasculitis of four to 30 years' duration that was unresponsive to a variety of medications were treated with pentoxifylline. Three patients experiences complete healing and remained free of active lesions while receiving the drug, four noted much improvement, and one had no change.

Cutaneous silica granuloma. A rare entity or rarely diagnosed? Report of two cases with review of the literature.

Cutaneous silica granuloma is a poorly understood, uncommon condition that may mimic cutaneous sarcoidosis. We describe two cases of this entity and their characteristic latency period (between the time of silica exposure to the time of clinical onset of granuloma). We also review the histologic and energy dispersive x-ray analysis data, which prove the diagnosis. This condition should be recognized as an occupational dermatosis as well as the result of past incidental cuts or abrasions, which result in the development of granulomas, many in old wound scars. Differentiation from cutaneous sarcoidosis is possible with polarized light microscopy and energy-dispersive x-ray analysis.

Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis.

BACKGROUND: We hypothesized that low-dose methotrexate treatment for patients with psoriasis would block purine biosynthesis at the step catalyzed by aminoimidazolecarboxamide (AICA) ribotide transformylase and would inhibit adenosine metabolism as evidenced by increased urinary levels of AICA and adenosine, respectively. Eight patients collected a 24-hour urine specimen on the day before their methotrexate dose and the next day during their methotrexate dose. Eight age- and sex-matched controls also collected a 24-hour urine sample. Urinary AICA and adenosine were assayed by spectrophotometric and radioimmune assays, respectively; means are reported as micromole per millimole of creatinine and were compared by the paired t test (1-tailed). OBSERVATIONS: Mean AICA excretion increased from 1.30 micromol/mmol on the day before to 1.85 micromol/mmol on the day during methotrexate dosing (P<.01). Mean adenosine values increased from 0.68 to 1.07 micromol/mmol, (P<.03). Controls had mean AICA and adenosine levels of 1.29 and 0.50 micromol/mmol, respectively. During the day of methotrexate dosing, patients had higher mean AICA and adenosine levels when compared with controls (P<.01). Mean AICA levels increased from 1.36 to 2.06 micromol/mmol (P<.025), and mean adenosine levels increased from 0.72 to 1.25 micromol/mmol (P<.025) in 5 patients showing improvement in clinical disease activity. In contrast, 3 patients with no change or worsening in clinical disease activity had smaller increases. CONCLUSIONS: Methotrexate treatment of patients with psoriasis inhibits AICA ribotide transformylase and adenosine metabolism. Since adenosine is a T-lymphocyte toxin, it may be partially responsible for the immunosuppressive effect.

Pemphigus vulgaris. Combined treatment with intravenous corticosteroid pulse therapy, plasmapheresis, and azathioprine.

A 13-year-old child is described who presented with generalized pemphigus vulgaris associated with extraordinarily high titers of circulating autoantibodies against the pemphigus antigen. Because of the lack of response to treatment with reasonably high doses of oral corticosteroids, as well as the very high titer of circulating autoantibodies observed, this patient was treated with intravenous corticosteroid pulse therapy followed by plasmapheresis and then by combination immunosuppressive therapy (prednisone and azathioprine). A rapid clinical response was induced, correlating with reduction and subsequent elimination of the circulating pemphigus autoantibodies. Using such combination therapy, a remission of 12 months was achieved, and prednisone therapy was completely, albeit temporarily, tapered and then discontinued. Subsequent disease flare was then easily controlled with a short course of low-dose oral corticosteroid therapy.

Leukocytoclastic vasculitis.

Patients with leukocytoclastic vasculitis have purpuric, palpable lesions, most commonly on the lower part of the legs. Systemic involvement, particularly of the kidneys, is found frequently. Characteristic pathological features include necrosis of small vessels within the dermis, infiltration by polymorphonuclear leukocytes within and around the vessel walls, hemorrhage, and occasionally thrombosis. Immunofluorescence study frequently shows granular deposits of immunoglobulins and complement in vessel walls. Etiologic agents that have been implicated include infection, foreign proteins, chemicals, drugs, and a variety of diseases. The mechanism causing tissue damage is thought to be mediated by immune complexes, although specific antigens have only occasionally been unequivocally identified. Treatment includes bedrest, corticosteroids, and sometimes, cytotoxic agents.

Sun-induced aging. Clinical and laboratory observations in man.

Chronic sun exposure can result in numerous changes in human skin, particularly the skin of fair-skinned individuals. These changes include wrinkling, elastosis, actinic keratoses, irregular pigmentation, telangiectasia, and skin cancer. Most of these alterations had formerly been considered to be caused by UVB wavelengths, which are the wavelengths probably most responsible. However, a number of recent studies have demonstrated that UVA can also cause burning, elastosis, and skin cancer. Thus, individuals exposed to intense UVB from sunlight coupled with intense UVA from suntan parlors are likely at increased risk.

Nails in systemic disease.

Nail abnormalities secondary to systemic disease are important to the dermatologist because they are readily examined and may be the initial signal that systemic disease may be present. Some of the abnormal nail findings represent part of a symptom complex that may be useful in physical diagnosis. The knowledge of the correct onychopathologic etiology may give the patient the correct nail prognosis and may prevent institution of possible incorrect lengthy and costly treatment regimens. In this article, nail signs are grouped according to the characteristics of the change and according to systemic diseases producing signs.