A multicenter study of leukocytapheresis in rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA) that is refractory to disease modifying antirheumatic drugs (DMARDs), we conducted a prospective, multicenter, open-label clinical trial. METHODS: We enrolled 38 active RA patients, including 32 patients who showed an inadequate response to > or = 2 DMARDs and 6 patients with rapidly progressive RA. All patients continued drug therapy and were treated with 5 LCAP sessions conducted at 1-week intervals. The clinical response was evaluated at baseline before starting LCAP and at 4 weeks after the completion of all the LCAP sessions using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of the European League Against Rheumatism (EULAR). RESULTS: Of the 35 patients who fulfilled the study's eligibility criteria, 24 (69%), 10 (29%), and 23 (66%) patients achieved 20% (ACR20), 50% (ACR50), and DAS28-C-reactive protein (CRP) EULAR improvement, respectively. The mean DAS28-CRP score of the 35 patients decreased significantly from 5.99 +/- 0.92 at baseline to 4.54 +/- 1.39 after treatment. Comparison analysis of the ACR20 responders and non-responders to LCAP revealed that 22 of 24 responders (92%) concomitantly received methotrexate, whereas significantly fewer, that is, 6 of 11 non-responders (55%) received methotrexate. Less frequent and transient mild-to-moderate adverse events, including nausea and headache, were seen in 12 of 189 LCAP sessions (6.3%). CONCLUSION: These results demonstrate the usefulness of LCAP in combination with DMARDs, particularly methotrexate, as an effective and safe treatment for refractory RA.

Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis.

To find a less-invasive and lung-specific clinical biomarker, we measured serum levels of surfactant proteins A and D (SP-A and SP-D) by sandwich enzyme-linked immunosorbent assays in 42 patients with progressive systemic sclerosis (PSS) to evaluate their significance in relation to the presence of interstitial lung disease (ILD) and to assess their diagnostic merits. The patients were divided into two groups based on findings by chest computed tomography (CT): 30 patients with ILD (CT-positive ILD group), and 12 patients without any lung abnormalities (CT-negative ILD group). The CT-positive ILD group was further divided into two groups: 24 patients with ILD detectable by chest plain radiography (X-ray-positive ILD group) and six patients with ILD showing no abnormality (X-ray-negative ILD group). The levels of SP-A and SP-D in sera were significantly higher in the CT-positive ILD group than in the CT-negative ILD group. They were also significantly higher in the X-ray-positive ILD group than in the CT-negative ILD group. In the X-ray-negative ILD group, their levels were higher than those of the CT-negative ILD group. We next estimated sensitivity and specificity of SP-A, SP-D, and X-ray for detecting ILD on CT. Sensitivity of SP-D was high (77%) as well as that of X-ray (80%), whereas SP-A showed a low sensitivity (33%). Remarkably, five of six patients in the X-ray-negative ILD group showed SP-D concentrations over its cut-off level, thereby demonstrating that an SP-D assay contributes to the detection of ILD overlooked by X-ray. Moreover, a combination of X-ray and SP-D dramatically increases sensitivity to 97%. Specificity of SP-A, SP-D, and X-ray to the CT-negative ILD group was 100%, 83%, and 100%, respectively. In conclusion, this study indicates that elevated levels of serum SP-A and SP-D reflect well the presence of ILD and that the combination of SP-D and X-ray contributes to reduce the risk of clinicians overlooking ILD complicated by PSS, although a repetition in another set of subjects is needed to confirm these indications.

High expression of macrophage migration inhibitory factor in the synovial tissues of rheumatoid joints.

Macrophage migration inhibitory factor (MIF) plays an important role in inflammation and immunity via autocrine/paracrine and endocrine routes. We examined the presence of MIF in the synovial fluids of rheumatoid arthritis (RA) patients. The content of MIF in the synovial fluid was quantitated by enzyme-linked immunosorbent assay which revealed that the concentration of MIF for RA patients was 85. 7+/-35.2 ng/ml (mean+/-SD) (n=25). In comparison, the concentrations for osteoarthritis patients and normal volunteers were 19.5+/-5.3 ng/ml (n=12) and 10.4+/-1.1 ng/ml (n=5), respectively. The expression of MIF mRNA and presence of MIF protein in the synovial tissues of RA were demonstrated by Northern blot and Western blot analyses, respectively. Immunohistochemical analysis revealed that positive staining was largely observed in the cytoplasm of infiltrating T lymphocytes, which might be the major source of MIF detected in the synovial fluids. The pathophysiological role of MIF in RA remains to be elucidated; however, the present results for the first time suggest the possibility that MIF is involved in the potentiation of inflammatory and immunological responses in rheumatoid joints.

[Neuro-psychiatric involvement in primary Sjögren's syndrome].

Neuro-psychiatric involvement in primary Sjögren's syndrome (PSJS) has been summarized according to the literature. Sjögren's syndrome is an autoimmune disorder with a predilection for multi-system involvement. Recently, disorders of the peripheral nervous system (PNS) and central nervous system (CNS) in PSJS, as well as, other organ involvement has been reported increasingly. However, CNS involvement, including the symptoms mimicking multiple sclerosis in PSJS is a controversial issue. There is discrepancy in the frequency of CNS involvement in PSJS among investigators. As for psychiatric manifestations in PSJS, descriptions have been made by many investigators. Depression and anxiety are the most common psychiatric manifestations in PSJS. About 10% of the patients with SJS have a neuropathy which tends to predilect for trigeminal nerve involvement. Further investigations elucidating the mechanisms of neuro-psychiatric involvement in PSJS is required.

Severe hepatic involvement without inflammatory changes in systemic lupus erythematosus: report of two cases and review of the literature.

Hepatic diseases in systemic lupus erythematosus (SLE) are not rare, but liver biopsies of those cases are usually reported as chronic hepatitis or steroid-induced steatosis. We describe two unusual patients with active SLE who displayed liver dysfunction without inflammatory changes or associated with drug administration. A liver biopsy in case 1 showed massive hepatic cell damage resulting in acute hepatic failure. In case 2, the liver specimen revealed diffuse fatty degeneration without symptoms specific to liver dysfunction. No inflammatory cell infiltrate was observed in the liver tissue of either patient. After steroid pulse therapy (case 1) and the administration of 60 mg/day of prednisolone (case 2), liver function improved in parallel with the stabilization of the other manifestations of SLE. No other causes for liver damage except for SLE were observed in either case. Therefore it is supposed that the liver impairments in these cases were one manifestation of SLE.

Treatment of systemic lupus erythematosus with lobenzarit: an open clinical trial.

An open clinical trial was designed to examine the efficacy and safety of lobenzarit (CCA), a newly developed disease modifying anti-rheumatic drug, in combination with conventional treatment with prednisolone for patients with systemic lupus erythematosus (SLE). Fifteen patients with SLE were given CCA 40 mg b.i.d. for the first 2 weeks, 80 mg b.i.d. for the next 4 weeks, and 80 mg t.i.d. or b.i.d. until the end of the 12-month trial, in addition to prednisolone, whose doses were kept unchanged throughout the trial. The patients' clinical responses to CCA, including alterations in various laboratory parameters and the development of complications, were evaluated at the end of 12 months. Fourteen of the 15 patients completed the 12-month trial. Significant increases in the white blood cell count and CD4/CD8 ratio, as well as decreases in serum anti-DNA antibody, were noted after the trial. Five patients presented with adverse effects, including mild liver dysfunction, gastrointestinal symptoms and dizziness. Only one patient who developed dizziness withdrew at 9 months. Eleven patients could be reevaluated after discontinuation of CCA, and only 2 of them have experienced recurrence of active disease 6 months after discontinuation. In one additional patient who had not responded to prednisolone 35 mg daily, administration of CCA resulted in improvement of the disease activity. These results indicate that CCA in combination with corticosteroids is a useful adjunct in the treatment of SLE. A placebo-controlled study will be necessary to confirm these results.

3 cases of anti-Scl-70 (topoisomerase I) antibody associated with central nervous system lupus without renal disorder.

We describe 3 cases of systemic lupus erythematosus (SLE) associated with anti-Scl-70 antibody. Common symptoms were central nervous system disorder, discoid rash, lymphadenopathy, and no renal disorder. Two of 3 cases showed some symptoms of scleroderma but could not be diagnosed as such. Although further followup is required to determine if scleroderma develops, these unique symptoms might be a subtype of SLE or a lupus-like syndrome characterized by symptoms and anti-Scl-70 antibody.

Parkinson-like symptoms as a manifestation of systemic lupus erythematosus.

A 42-year-old Japanese woman with systemic lupus erythematosus (SLE) developed Parkinsonian-like movements. Steroid pulse therapy was most effective and additional anti-Parkinsonian drugs were not required. Although psychosis, seizures and meningitis are common central nervous system (CNS) manifestations in SLE patients, Parkinsonian-like symptoms are extremely rare. The putative genesis and treatment of CNS lupus are discussed.

[Clinical evaluation and application of new ARA criteria for rheumatoid arthritis].

At the 51st American Rheumatism Association meeting, a new ARA criteria for rheumatoid arthritis (RA) was proposed. According to this criteria, both the sensitivity and the specificity have improved to 93% and 90%, respectively. We investigated the adequacy of this criteria by applying this to Japanese patients with RA and control subjects with rheumatic diseases, other than RA. By using new criteria the sensitivity was decreased from 89.6% to 85.3% and the specificity was increased from 82.7% to 92.8%. The factors for the decreased sensitivity of the new criteria were 1) morning stiffness which became more than 1 hour, 2) the number of swelling joints increased from one to three and 3) radiologic changes, which were restricted to the hand only. On the other hand, the factors for increased specificity were (1) morning stiffness, (2) deletion of criterion of joint pain and (3) joint swelling. According to the classification tree method, the sensitivity and the specificity were 96.3% and 90.0% respectively in this study. Continued nationwide study on this new criteria, whether this is applicable and useful to classify Japanese patients with RA is necessary.

[A case of systemic lupus erythematosus (SLE) developing pan-dysautonomia].

A 43-year-old woman who had been diagnosed as primary Sjögren's syndrome since 1986 developed severe constipation, urinary retention, dizziness at standing and polyarthralgia in February, 1990. Laboratory tests revealed proteinuria, hypocomplementemia and high titer of anti-DNA antibody. Diagnosis of SLE was made and she was admitted to our hospital on April 2, 1990. Physical examination on admission showed that she also had asymmetric pupils, impairment of sweating, orthostatic hypotension, neurogenic bladder, gastro-intestinal dysmotility and the diminution of R-R interval variability during deep breathing on the electrocardiogram. These findings suggested that she had pan-dysautonomia but there were no signs of motor and sensory disturbance. Because other diseases such as diabetes mellitus and amyloidosis which induced dysautonomia could be ruled out, her pan-dysautonomia seemed to be due to SLE. After the treatment with steroid pulse therapy, most of her dysautonomia improved rapidly. However, some of the disturbance had persisted for a long time. Pan-dysautonomia has been rarely reported as a complication of SLE, and high dose of steroid therapy at the early stage should be considered.

[Systemic lupus erythematosus associated with benign intracranial hypertension: a case report].

A case of systemic lupus erythematosus (SLE) with benign intracranial hypertension (BIH) is reported. A 41-year-old male with a history of SLE starting in 1982 was admitted to our hospital in December 1989 because of headache and vertigo. Laboratory examinations on admission showed proteinuria, mild anemia, and positive antinuclear and anti-Sm antibodies. No abnormal findings except high pressure of 350 mmH2O were observed in his cerebrospinal fluid (CSF). Fundoscopic examinations showed marked bilateral papilledema and retinal bleeding. Brain CT, MRI and angiography revealed diffuse brain edema without space occupying lesion and cerebrovascular diseases. Because there were no diseases such as endocrinological disorders, severe anemia, and no history of the administration of drugs which might cause intracranial hypertension, the diagnosis of BIH was made. Subsequently, he was treated with intravenous methylprednisolone therapy and osmotic diuretics and his clinical symptoms and pressure of CSF gradually improved. The decrease of CSF adsorption was observed with RI cisternography in our case. Psychosis, seizures and meningitis are common CNS manifestations in SLE patients. But BIH is very rare and its cause is unclear. Only 17 cases of SLE with BIH have been reported. The pathogenesis and treatment of BIH in SLE patients were discussed in this paper.

Elevated gene expression of argininosuccinate synthetase in peripheral lymphocytes from systemic lupus erythematosus (SLE) patients.

Argininosuccinate synthetase (ASS) is a rate-limiting enzyme of urea cycle and functions primarily in the liver, whereas ASS activity is hardly detected in normal lymphocytes. In this study, we examined the level of ASS gene expression in peripheral blood lymphocytes (PBL) from human SLE patients by amplification of reverse-transcribed mRNA using the polymerase chain reaction. We have demonstrated that (a) approximately 40% of SLE patients exhibited 2.5 to 5 times higher expression of ASS gene in PBL than those of healthy PBL and (b) the elevation of ASS gene expression of PBL significantly correlates with the active pathogenesis of SLE patients according to the criteria of Japanese Ministry of Health and Welfare (p < 0.001 by student's two-tailed t-test). Thus, it is suggested that ASS gene expression is a promising marker of hyperactivated lymphocytes uniquely generated in patients with systemic autoimmune disease.

[Analysis of anti-DNA antibody in sera from patients with systemic lupus erythematosus by isoelectric focusing with respect to autoantibody isotype and immune complex].

Systemic lupus erythematosus (SLE) is an autoimmune disease manifested by the production of autoantibodies which leads to an array of clinical symptoms. Among these autoantibodies, anti-DNA antibodies play a major role, since resulted DNA/anti-DNA immune complexes(IC) cause glomerulonephritis and other autoimmune local lesions in SLE. In this report, spectrotypes of anti-DNA antibodies of IgG, IgA and IgM classes, and IC were studied by isoelectric focusing. The size of IC was also studied. Anti-DNA autoantibodies in the sera of SLE patients were found mainly in IgG class, however, those of IgA and IgM classes were detected as minor subpopulations. By electrofocusing, both IgA and IgM anti-DNA antibodies were focused to relatively restricted acidic regions. In contrast, IgG anti-DNA antibodies were focused to two distinct pH regions; one was the acidic region similar to that IgA and IgM antibodies migrated (pH 3.2 to 6.0), and the other to far basic region between pH range of 7.8 and 10.0. IC was focused to the same basic region as a fraction of IgG migrated. Anti-DNA antibodies of IgG class, especially those focused to alkaline pH region (cationic antibodies) bound to phenylalanine (PH) column with high affinity. From these results, it was inferred that anti-DNA antibodies of IgG classes, especially those having high basic charge (cationic antibodies) showed a tendency to form IC and that the cationic antibodies may participate in the pathogenesis of tissue injury, especially of glomerulonephritis, in SLE.

[A case of rheumatoid arthritis developing pemphigus-like skin lesion during treatment with bucillamine].

Bucillamine is a useful medication for treatment of rheumatoid arthritis (RA) but some patients develop side effects from it. Here, we report a patient with RA developing a pemphigus-like skin lesion during treatment with bucillamine. A 55 year old woman with RA (stage III, class II) had been treated with bucillamine in our hospital since September 1988. Her symptoms of RA had gradually improved after administration of bucillamine but the generalized skin rash with itching developed in June 1989. Skin biopsy revealed spongiosis, the infiltration of lymphocytes in the epidermis and inter-cellular deposition of IgG. These findings were consistent with the histological change of pemphigus. Since symptoms of the skin disappeared two months later after the discontinuation of bucillamine. We considered that her pemphigus-like lesion was induced by this drug. D-penicillamine is one of the drugs which induce pemphigus. Though the mechanisms of this side effect have not been clear, it is thought that autoantibody induced by D-penicillamine could be one of the cause of pemphigus. Because the chemical structure of bucillamine is similar to that of D-penicillamine, the autoimmune mechanisms may also play a role in the onset of the pemphigus-like lesion in this case.

[Pneumoperitoneum without perforation of the gastrointestinal tract in a patient with systemic lupus erythematosus].

Pneumoperitoneum often occurs after the perforation of the gastrointestinal tract. However, pneumoperitoneum without the perforation has been reported as one of the complications of collagen diseases, the cause of which is usually the rupture of pneumatosis cystoides intestinalis (PCI). PCI is sometimes observed in the patients with scleroderma and mixed connective tissue disease but rarely in the patients with systemic lupus erythematosus. We reported here a case of systemic lupus erythematosus developed the pneumoperitoneum without the perforation of gastrointestinal tract. A 51-year-old female who had been diagnosed as systemic lupus erythematosus and taken steroid for 12 years, visited our hospital because of general malaise. She had no abdominal symptoms but the roentgenographic examinations revealed the pneumoperitoneum. The laparotomy was performed and there were no findings of the perforation of the gastrointestinal tract. Because PCI is hardly recognized macroscopically after the rupture and the pneumoperitoneum due to PCI is often asymptomatic, we considered the cause of the pneumoperitoneum in this case was the rupture of PCI. The mechanisms of the formation of PCI in patients with collagen diseases were also discussed in this paper.

[Clinical course and prognosis in SLE patients with pulmonary hypertension: a comparative study with primary pulmonary hypertension].

Recently pulmonary hypertension (PH) has been recognized as one of life threatening complications which determine the prognosis of patients with systemic lupus erythematosus (SLE). Clinical aspects and pathology in patients with SLE complicated by PH (SLE-PH) have been reported to have a close similarity to those in patients with primary pulmonary hypertension (PPH), the prognosis of which is very poor in general. However, the long-term prognosis for patients with SLE-PH is not clear yet. Mainly because of some technical limitations for determining the severity of the PH, long-term follow-up studies have been inconclusive. In this study, 7 patients with SLE-PH and 6 patients with PPH were studied by using two-dimensional echocardiography. The interventricular septal curvature (R) was measured from the parasternal short axis view and the reciprocal value (1/R) was applied as a severity index of the PH. In 4 patients with SLE-PH and 6 with PPH, pulmonary arterial pressure was measured by cardiac catheterization concomitantly. There were no significant differences in 1/R and pulmonary arterial pressure between the two groups when PH was diagnosed for the first time. In the PPH group, the mean period of follow-up study was 25.3 months and all of the patients died during that period. In SLE-PH group, the mean period of follow-up study was 50.6 months, and only 3 patients (43%) died during that period. No patients in the PPH group showed improvement in 1/R, but 3 patients with SLE-PH improved in 1/R during a long follow-up period (60, 96 and 103 months respectively). Thus, the prognosis for SLE-PH was better than that for PPH, and there were some differences in the course and worsening behavior of PH in SLE-PH compared with that in PPH during the long-term follow-up study with reference to the echocardiographic investigation using 1/R value.

[Thermography of collagen diseases with Raynaud's phenomenon].

In forty-four patients with collagen diseases accompanied with Raynaud's phenomenon(systemic lupus erythematosus(SLE)10, progressive systemic sclerosis(PSS)15, primary Sjögren's syndrome(PSJS)18 and mixed connective tissue disease(MCTD)1), we analyzed the thermography of fingers after thermal stimulation with cold water(15 degrees C, 30 seconds). In normal controls, the temperature of the distal points of fingers was higher and recovered more quickly than that of the proximal points(proximal interphalangeal joint; PIP). But in the patients with Raynaud's phenomenon, the temperature of distal point of fingers was lower and recovered more slowly than that of proximal points. Because the difference of the temperature between the distal and the proximal points (DP)is a good parameter to distinguish these two thermographic patterns, we analysed DP. DP is less influenced by room temperature than the temperature of fingers and the recovery temperature after thermal stimulation which have been used as indicators of Raynaud's phenomenon. DP in the normal controls was significantly higher than that in the patients. DP in PSS was lower than that in SLE and PSJS, and statistically associated with the markers of disease activities, such as erythrocyte sedimentation rate, titers of anti-RNP antibody and diffusing capacity of lung. These results show that thermographic pattern and the value of DP are the useful indicator of severity of Raynaud's phenomenon.