Individual pharmacodynamics assessed by antilymphocyte action predicts clinical cyclosporine efficacy in psoriasis.

BACKGROUND: Cyclosporine (INN, ciclosporin) use for psoriasis has been proposed and clinically examined. However, individual variation in cyclosporine efficacy is currently observed. To evaluate individual therapeutic potency of cyclosporine, pharmacodynamic approaches were performed with use of peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. METHODS: Cyclosporine effects on PBMC-blastogenesis were examined in 33 patients with psoriasis. The drug concentration that gave 50% inhibition of mitogen-stimulated PBMC proliferation in vitro (IC50, in nanograms per milliliter) was evaluated in each patient. Cyclosporine was administered at an initial dose of 5 mg/kg/day, and the dose was tapered for 16 weeks to 3 mg/kg/day. The recovery rate in the psoriasis area and the severity index (PASI) 16 weeks after cyclosporine therapy began was measured. RESULTS: Cyclosporine IC50 values in 33 patients deviated widely, from 0.1 to 120.6 ng/ml. We classified these patients into two groups on the basis of their PBMC sensitivity to cyclosporine with use of the median cyclosporine IC50 (3.0 ng/ml) of these patients as the cutoff point. The PASI recovery rate after cyclosporine therapy in the patients with high sensitivity was significantly higher than that in the patients with low sensitivity (p < 0.0007). Moreover, a significant negative correlation between the IC50 and the PASI recovery rate was observed in these 33 patients (r = -0.73; p < 0.0001). Blood trough levels and side effects of cyclosporine were not significantly different between the two patient groups. CONCLUSIONS: The results showed that we could use PBMCs to pharmacodynamically predict the patients with a poor response to cyclosporine therapy. These patients may require larger doses of cyclosporine or alternative approaches to treatment. The patients with PBMCs sensitive to cyclosporine should be evaluated for treatment with smaller doses of the drug to avoid serious side effects.

Immunosuppressant pharmacodynamics on lymphocytes from healthy subjects and patients with chronic renal failure, nephrosis, and psoriasis: possible implications for individual therapeutic efficacy.

BACKGROUND: In organ transplantation, patients with peripheral blood mononuclear cells (PBMCs) that exhibit resistance to cyclosporine (INN, ciclosporin) or glucocorticoids in vitro are refractory to therapy based on these drugs in vivo. However, detection or distribution of the resistant patients with immunologic disorders remains to be documented. METHODS: Drug sensitivity tests were performed with PBMCs from four subject groups: 69 healthy subjects, 100 patients with chronic renal failure, 38 patients with nephrosis, and 51 patients with psoriasis. The values for the concentration that produces 50% lymphocyte-mitosis inhibition (IC50) of the drugs on PBMC blastogenesis were estimated, and individual variations or group differences in the IC50 values were examined. RESULTS: The median cyclosporine IC50 values of the four subject groups were similar, but large individual deviations in the IC50 values were observed. Individual differences in prednisolone IC50 values were spread from 1 to 3500 ng/ml. When compared with healthy subjects, a significantly large number of the patients with chronic renal failure group exhibited low responses to prednisolone (p < 0.04). In contrast, no significant difference in the methylprednisolone IC50 was observed among the groups. Normal upper thresholds for IC50 values of these drugs were estimated from the mean + 2 standard deviations (SD) of the IC50 values of healthy PBMCs, and the patients with IC50 values above these levels were considered to be resistant. The incidence of resistant patients with nephrosis or psoriasis was similar to that of healthy subjects; however, the incidence of cyclosporine- or prednisolone-resistant subjects with chronic renal failure was significantly higher (p < 0.04). Significant correlations between PBMC sensitivity to cyclosporine in vitro and clinical efficacy of the drug in vivo were observed in renal transplant recipients and in patients with psoriasis. CONCLUSIONS: A large subset of patients with chronic renal failure showed PBMC resistance to cyclosporine and prednisolone. Hyperresistant patients have a high risk of being refractory to immunosuppressive therapy with one of these drugs. Alternative treatment should be considered according to the individual drug-sensitivity data.

Characteristic magnetic resonance imaging findings in Machado-Joseph disease.

OBJECTIVE: To clarify the characteristic magnetic resonance imaging (MRI) findings in patients with Machado-Joseph disease (MJD) diagnosed by genetic analysis. PATIENTS AND METHODS: Using MRI, we examined 31 patients genetically diagnosed as having MJD, 20 patients with sporadic olivopontocerebellar atrophy, and 26 control subjects. RESULTS: The MRIs of patients with MJD disclosed remarkably reduced width of the superior cerebellar peduncles, atrophy in the frontal and temporal lobes, diminished transverse diameter of the globus pallidus, and decreased anteroposterior and transverse diameters of the pons, which correlated with the width of the middle cerebellar peduncle. The width of the superior cerebellar peduncles also correlated with the diameter of the dentate or red nucleus in patients with MJD, but not in controls or in patients with sporadic olivopontocerebellar atrophy. On T2- and/or proton-weighted axial MR imaging, a high signal intensity in the transverse pontine fibers was observed in 14 (45.2%) of 31 patients with MJD and in all patients with sporadic olivopontocerebellar atrophy, but not in any controls. CONCLUSION: Affected afferent and efferent cerebellar tracts and atrophy of the frontal and temporal lobes and globus pallidus are characteristics of MRI of patients with MJD.

Relationship between lymphocyte cyclosporin sensitivity and clinical progress of psoriasis.

Cyclosporin (CYA) is a therapeutic agent used in the treatment of psoriasis vulgaris. However, the effectiveness of CYA therapy varies among patients. In the present study, due to the fact that CYA mainly acts on lymphocytes, we hypothesized that a measurement of the sensitivity of lymphocytes to CYA in vitro (IC50) could be applied to patients with psoriasis vulgaris to determine therapeutic success. We measured IC50 levels of 32 patients presenting with psoriasis prior to CYA administration, and classified them into three groups according to IC50 levels: favorable, moderate and low sensitivity. CYA sensitivity levels were correlated with the degree of improvements in psoriasis area and severity index (PASI) scores, CYA dosage and occurrence of side-effects (hepatopathy and nephropathy). Results showed the degree of improvement in PASI scores differed significantly between the favorable and low sensitivity groups (P < 0.05). Furthermore, CYA dosage was lowest in the favorable sensitivity group and highest in the low sensitivity group. Moreover, hepatopathies and nephropathies were detected in the low and moderate sensitivity groups, but not in the favorable sensitivity group. These results suggest that the effectiveness of CYA therapy as a treatment of psoriasis vulgaris is affected by the sensitivity of lymphocytes in each patient.

CAG repeat length and disease duration in Machado-Joseph disease: a new clinical classification.

To evaluate the clinical characteristics of Machado-Joseph disease (MJD) with reference to CAG repeat length and disease duration, we analyzed neurologic findings in 108 patients from 84 families. The majority of MJD patients presented with an ataxic gait as the initial symptom. Dysarthria and nystagmus were observed from an early stage. Bulging eyes, muscle atrophy and bradykinesia developed later. Patients with a shorter CAG repeat length or later onset had more frequent involvement of proprioceptive sensory deficit. Incidence of abnormal reflexes, tones, and proprioceptive sensation was not associated with disease duration, but with CAG repeat length. Based on these results, we propose a new clinical classification: type A (juvenile type), with hyperreflexia and dystonia, but without a proprioceptive sensory deficit; type C (adult type), with hyporeflexia and a proprioceptive sensory deficit, but without dystonia; and type B (intermediate type), the remaining patients with a mixed presentation.

Contact dermatitis due to topical steroids with conceivable cross reactions between topical steroid preparations.

Steroids are usually employed to inhibit inflammation. However, allergic contact dermatitis has been reported with topical steroids. We have experienced contact dermatitis due to active ingredients of topical steroids in 11 patients. Therefore, we make it a rule to carry out the patch test with as many topical steroids as possible. Five patients were confirmed to be positive to several corticosteroids in the patch test. Papers on patients allergic to steroids indicate that some patients react to several. It is difficult to evaluate whether the reaction is caused by multisensitivity or by cross reaction. However, even if steroids differ in type, they may often cause cross reactions when they have a common chemical structure. Considering this chemical structure, we tried to classify steroids reported to cause allergy in patients into the following four types: 1) The type recognizing betamethasone and/or dexamethasone. Regardless of whether the methyl group at the C-16 position of the D ring is on the alpha or beta side, the size of the blocking group of the hydroxy residue seems to be associated with the reaction. 2) The type in which a chlormethylketone group at the C-17 position of the D ring seems to be associated with the reaction. 3) The type in which a cis-diaxial-diol side chain in the alpha side of C-16 and C-17 positions of the ring D or its ketal blocking group seems to be associated with the reaction. 4) The type in which the size of the ester protecting the hydroxy group at the C-17 alpha position seems to be associated with the reaction. In patients showing a reaction, there may be receptors recognizing each steroid. If the steroid administered is changed, the receptor appears to recognize the changed steroid in a relatively short period. Thus the receptor may not be constant.

The relationship between angioblastoma (Nakagawa) and tufted angioma: report of four cases with angioblastoma and a literature-based comparison of the two conditions.

We report four recent cases of angioblastoma (Nakagawa). Histopathologic examinations of all cases revealed dispersed islets of clear marginal lobules of varying sizes in the dermis. Neoplastic endothelioid cells with moderate atypia and enlarged capillaries containing erythrocytes were found in the conglomerates. Recently, the features of this disease have been compared to the tufted angioma that has been reported in Europe and the U.S. Our evaluation suggests that these two diseases are very likely the same. We suggest that this disease should be called "angioblastoma" in agreement with the first report of this disease by Nakagawa.

A unique case of cutaneous calcinosis with transepidermal elimination.

A case of cutaneous calcinosis with unique clinical and histological features which occurred on the cheek of a 14-year-old girl, is reported. Our case had no abnormal findings in laboratory data. Serum calcium and phosphate were normal, there was no underlying disease, and the possibility of self-inflicted dermatoses was denied. Transmission electron microscopy and X-ray microanalysis showed calcium and phosphate deposited around collagen fibers, which were eliminated from the epidermis.

Staphylococcal scalded skin syndrome in a healthy adult.

We report a case of staphylococcal scalded skin syndrome (SSSS) in a 65-year-old healthy woman. Fever, purulent conjunctivitis, and exfoliation of the skin in the gluteal region were noted. A scarlatiniform rash was observed on the body, and this erythema was followed by generalized desquamation. Staphylococcus aureus was isolated from her eye discharge, posterior nasopharynx, and the erosive surface of the skin. All the investigated strains produced exfoliative toxin B, but none produced toxic shock toxin-1 (TSST-1) or enterotoxin. The patient was treated with antibiotics and fluid supplementation, resulting in subsidence. This case is thought to have been caused by an abortive form of SSSS or a scarlatiniform variant, which is very rare in healthy adults.

Evaluation of acceleration plethysmograms in dermatology--efficacy of lipo PGE1 preparations against herpes zoster and neuralgia following herpes.

Reports published in recent years indicate that administration of lipo PGE1 is effective against herpes zoster and neuralgia following herpes. However, there are presently no standards to objectively assess efficacy. We therefore looked into the possibility of achieving this goal by using an acceleration plethysmograph. The results showed a significant difference in the rate of change of pulse waves after initiation of drip infusion as compared to before drip infusion among the effective group, the control group, and the non-effective group. This method appears to be useful to objectively assess both the analgesic effects of lipo PGE1 and the efficacy of drugs in general, based on data analysis. Our results suggest that investigations using this method may be able to predict the therapeutic effects of vasodilators and analyze hemodynamic disorders of the skin.

Staphylococcal scalded skin syndrome developing during burn treatment.

We report a case of staphylococcal scalded skin syndrome (SSSS) in a 5-year-old girl who had been hospitalized for burn treatment. When she developed an upper respiratory tract infection, she manifested extensive erythema and exfoliation. There was a purulent discharge from the ulcer caused by the burn, and exfoliation was observed in the surrounding area. Based on clinical symptoms and laboratory data, SSSS was diagnosed and treated with antibiotics, resulting in subsidence. Staphylococcus aureus was isolated from the posterior nasopharynx and the skin erosion and was proved to produce exfoliative toxin A (ETA). Infection from an asymptomatic carrier of an ET-producing strain was suspected, but we failed to identify the origin, in spite of a thorough inspection of the mother, nurses, and physician. SSSS is occasionally reported as a hospital-acquired infection. We should study the frequency of asymptomatic carriers of ET-producing strains so that we can formulate strategies to prevent such infections.

A case of pyoderma gangrenosum on the stump of an amputated right leg.

We present here a case of pyoderma gangrenosum (PG) on the stump of an amputated leg. The patient was a 69-year-old woman who had both of her legs amputated due to acute arterial occlusion. An ulcer first appeared nine years later, after which point it continued to fluctuate in size. Complications included regional blood flow disorder at the amputated stump, diabetes, and secondary infection. Despite various therapies, the ulcer exacerbated, and hypoproteinemia, increased CRP, and fever were confirmed. The patient was diagnosed as having PG based on her clinical symptoms and because the ulcer did not respond to various therapies. The ulcer improved significantly in response to administration of 40 mg/day of prednisolone, and complete epithelialization was later achieved. Given the presence of multiple complications, it was extremely difficult to confirm PG. Therefore, it is important for physicians to consider PG as one of the causes of intractable ulcers.

Changes in plasma serotonin concentration and acceleration plethysmograms in patients with Raynaud's phenomenon after long-term treatment with a 5-HT2 receptor antagonist.

High blood serotonin concentrations have been reported in patients with Raynaud's phenomenon and a relationship has been suggested. Because of the difficulty in evaluating Raynaud's phenomenon objectively, a possible correlation between blood serotonin concentrations and clinical findings has not yet been evaluated. We measured plasma serotonin concentrations and acceleration plethysmograms (APG) before and one year after administration of a serotonin receptor antagonist. Twenty-seven patients with either collagen disease or diseases associated with Raynaud's phenomenon were given a combined 5-HT2 and serotonin receptor antagonist, sarpogrelate hydrochloride. Plasma serotonin concentrations were determined before and after administration and the APG d/a value was measured as an index of peripheral hemodynamics. These values were compared with the clinical symptoms of the patients. After one year of treatment, the subjective symptoms improved in 59.3% of patients who has Raynaud's phenomenon. The pretreatment plasma serotonin concentrations of the study patients were significantly higher than those of the normal controls, but became significantly decreased following 5-HT2 administration. However, there was no clear-cut relationship with the clinical symptoms. The pre-treatment APG d/a value of the patients was significantly lower than that of the normal controls, although there was no significant difference after administration when analyzed as an entire group or in a subset of patients whose symptoms did not subjectively improve or worsened after one year of treatment. In the subset in whom the subjective symptoms improved, however, the value significantly increased following administration, suggesting an improvement in peripheral hemodynamics. These results suggest the possibility that APG can be used as an objective index of peripheral hemodynamics.

Two cases of confluent and reticulate papillomatosis: successful treatments of one case with cefdinir and another with minocycline.

The present report presents two cases of confluent and reticulate papillomatosis. Case 1 was a 24-year-old man who had suffered from skin eruptions for six months, and Case 2 was a 19-year-old woman who had had this disease for three days. In both patients, reticular dark brown papules, accompanied by mild keratosis and infiltration, spread from the trunk to the neck and upper arm. Direct light microscopy did not detect the presence of any fungi, and histopathological examinations confirmed hyperkeratosis, acanthosis, papillomatosis, and mild small-round-cell infiltration. Thus, these patients were diagnosed as confluent and reticulate papillomatosis. Neither one had diabetes or thyroid dysfunction. In Case 1, cefdinir was effective, and in Case 2, minocycline hydrochloride and ketoconazole were effective. To the best of our knowledge, this was the first documented case of confluent and reticulate papillomatosis responding to cefdinir.

Ultrastructural observation of epithelioid sarcoma.

Epithelioid sarcoma located in the right hip-to-thigh region of a 58-year-old female was studied by light microscopy, immunohistochemistry, and electron microscopy. Light microscopy revealed both light and dark cells among the tumor cells. Round, homogeneous, eosinophilic bodies were noted extracellularly and intracellularly. Extracellular bodies were similar in size to tumor cells and were not stained by PAS or Congo red. In contrast, intercellular bodies were PAS positive and diastase resistant. Tumor cells were positive for vimentin, keratin, and, partially, for epithelial membrane antigen. Ultrastructurally, tumor cells had numerous microfilaments with tonofibril-like arrangement, lipid droplets, and reticulogranular structure in their cytoplasm. The reticulogranular structure was similar to the tonofilaments recognized in degenerative tumor cells. Oval filamentous bodies were recognized in the stroma. They appeared to be very similar to colloid bodies derived from tonofilaments of keratinocytes. It was considered that the filamentous bodies corresponded to extracellular eosinophilic bodies and showed signs of fibrous necrosis of tumor cells. Intracellular eosinophilic bodies were considered to be lipid droplets.

A case of proliferative fasciitis in the abdominal region.

A 20-year-old woman complained of a subcutaneous nodule accompanied by spontaneous pain and tenderness in the right hypochondriac region approximately two weeks prior to initial evaluation. The spontaneous pain and tenderness gradually worsened. Histopathological examination revealed a proliferative lesion that extended from the deep dermis to the fatty tissue and consisted predominantly of stellate or spindle-shaped fibroblast-like cells intermingled with gangliocyte-like giant cells. Consequently, proliferative fasciitis was diagnosed. Our investigation revealed only 19 cases of proliferative fasciitis reported in Japan. The overall age range of them is 20 to 75 years (mean, 57.6 years). The lesion site in them is the head and neck in 10%, the trunk in 30%, and the extremities in 60%. It follows that the extremities are predominantly the site of proliferative fasciitis, and truncal lesions are relatively rare. It is rare for proliferative fasciitis to occur at a young age or in the abdominal region. We therefore examined the differences between proliferative fasciitis and similar disorders, namely proliferative myositis and nodular fasciitis, based on summaries of cases reported in Japan.

A case of drug eruption caused by the crude drug Boi (Sinomenium stem/Sinomeni caulis et Rhizoma).

We report a case of drug eruption caused by the crude drug Boi. A 41-year-old female patient had been diagnosed with chronic rheumatoid arthritis in the department of internal medicine. After ingestion of a decoction of the crude drug Boi for the alleviation of arthralgia, a slight fever developed, which was followed by systemic edematous erythema with itching. HPLC showed that the main components of the crude drug Boi are sinomenine and magnoflorine. The results of patch tests were negative for all oral drugs that the patient had been taking. Oral ingestion tests showed that the patient showed positive reactions to the as-is Boi boiling-water decoction and 1/10-volume sinomenine. Based on this, the drug eruption was judged to be caused by sinomenine. It is considered the first time that the causative component of a drug eruption was confirmed by oral ingestion tests with components of a crude drug of Kampo medicine (Sino-Japanese traditional medicine).

The occurrence of various collagen diseases in one family: a sister with ISSc, PBC, APS, and SS and a brother with systemic lupus erythematosus.

We encountered siblings who had collagen diseases and related symptoms. Case 1 was a 53-year-old woman who had limited cutaneous systemic sclerosis (ISSc) associated with primary biliary cirrhosis (PBC), antiphospholipid antibody syndrome (APS), and subclinical Sjögren's syndrome (SS). Case 2 was a 48-year-old man, her younger brother, with systemic lupus erythematosus (SLE) that developed at 32 years of age. Investigation of their family revealed that their mother had Raynaud's phenomenon, arthritis, and subclinical Sjögren's syndrome, and that another younger brother of Cases 1 and 2 had Raynaud's phenomenon and general fatigue. HLA analysis revealed that the sister and brother had some identical HLA antigens in common, including A2, A33 (19), B67, B44 (12), Cw7, DR2, DR6, DR52, and DQ1. The sister, brother and their mother had common HLA antigens including A2, B67, Cw7, DR2, and DQ1. Although Cases 1 and 2 shared the same HLA system, they presented different phenotypes of collagen disease.

Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease.

Machado--Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the MJD1 gene was identified as the cause of the disease. We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas normal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association with the clinical anticipation of the disease, a parent--child analysis showed the unidirectional expansion of CAG repeats and no case of diminution in the affected family. The differences in CAG repeat length between parent and child and between siblings are greater in paternal transmission than in maternal transmission. Detailed analysis revealed that a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission. On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.