Amyloidosis in rheumatoid arthritis. A study of 48 histologically confirmed cases

In a group of 269 patients with rheumatoid arthritis histological examination demonstrated amyloidosis in 48 cases, viz. in 7 post mortem cases, in 28 rectal biopsies, in 12 renal biopsies and in one liver biopsy. Examination for amyloidosis was carried out in all patients who had proteinuria, otherwise in non-selected patients with definite rheumatoid arthritis. Even through rectal biopsy is a valuable screening method, it should not be overestimated, because in 12 patients with renal biopsy positive for amyloid, the foregoing rectal biopsies had been negative. According to our experience the most valuable method for diagnosis of amyloidosis in rheumatoid patients is renal biopsy, whereas synovial biopsy is the least conclusive. This paper, according to our knowledge, is the first report on observations of a regression of the inflammatory activity of rheumatoid arthritis and nephrotic syndrome as well as a complete morphological regression of amyloidosis.     

Bucillamine induced pulmonary injury occurs with immunoglobulin decrease

We describe pulmonary involvement in 3 patients with rheumatoid arthritis treated with bucillamine. In all 3, synovitis was in remission. The common radiological characteristic was mottled dense infiltrates, in which were air bronchograms, in the bilateral central lung, sparing the periphery. Lung biopsies in 2 cases revealed organizing exudates in the alveolar ducts and alveoli, and cellular infiltration into alveoli and septa. Serum immunoglobulin (Ig) levels decreased markedly at the time of involvement. After discontinuation of bucillamine, lung injury resolved without exacerbation of synovitis and Ig levels increased. A mechanism involving decreased Ig concentration is suggested.     

'Progressive' versus 'indolent' idiopathic membranous glomerulonephritis

There is still controversy about safe and effective therapy for idiopathic membranous glomerulonephritis (MGN). Over 20 years, we have simply observed our patients clinically after diagnosis, and only used aggressive therapy with steroids in high dosage and azathioprine for 21 patients with progressive renal failure. The other 42 were thus classified as 'indolent' MGN. Those with 'progressive' MGN had heavier proteinuria and worse renal function on presentation, but the overlap was considerable. Patients with progressive MGN were treated after 1-4 years. All responded promptly, and 5 years after presentation all were alive, and only one was on dialysis. By 10 years, most were still alive, and of these most were off dialysis. In five patients, dialysis was delayed by several years. There were two deaths on dialysis, and three other deaths, mostly in older patients. All but one patient with indolent MGN remained stable on symptomatic treatment only, for at least 5 years after presentation. In many, proteinuria fell to insignificant levels over 4 years. In these remitting patients, there was a prevalence of thyroid disease (7), rheumatoid disease (3) and nephrotic presentation in pregnancy (4). After 6-10 years three patients developed worsening proteinuria and renal failure. Five older patients died from unrelated causes.     

Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients

BACKGROUND: Hepatitis C virus (HCV) infection has been described in association with various types of glomerular diseases, usually type I membranoproliferative glomerulonephritis and rarely membranous glomerulonephritis (MGN). In this article, we describe the first series of MGN exhibited in renal transplant patients and associated with HCV infection. METHODS: From January 1980 to December 1994, 2045 kidney transplantations were performed in our renal transplant units. A retrospective analysis demonstrated an overall 20% prevalence of HCV virus-positive patients; 409 transplanted patients were HCV positive (ELISA and RIBA). RESULTS: Fifteen patients developed an allograft MGN (3.66%) 24 months after renal transplantation. MGN appeared in the form of significant proteinuria (>1.5 g/24 h) with stable renal function. In all cases, graft biopsy demonstrated a thickening of the capillary wall, subepithelial electron-dense deposits, and IgG and C3 diffuse granular deposits along the basal membrane. Ten cases were considered de novo, two cases were considered recurrent MGN, and three cases were considered undetermined because the primary renal disease was chronic glomerulonephritis. All patients showed negative antinuclear antibodies and cryoglobulins, normal complement, and negative rheumatoid factors. During follow-up (an average of 2 years), 12 patients developed a progressive worsening of renal function, with increased serum creatinine and persistent proteinuria; 8 of the 12 patients returned to dialysis. Of the remaining three cases, two patients showed partial remission of nephrotic syndrome after high doses of steroids, and one patient persisted with stable renal function and proteinuria (<2 g/24 h.). CONCLUSIONS: In summary, HCV is preferentially associated with MGN in renal transplant patients, rather than with membranoproliferative glomerulonephritis as in the normal adult population. MGN associated with HCV infection has a similar clinical picture and outcome to posttransplant idiopathic de novo MGN, with persistent massive proteinuria and progressive deterioration of renal function.     

Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis

OBJECTIVE: To evaluate aspects of the natural history of AA amyloidosis complicating juvenile rheumatoid arthritis (JRA), and its response to therapy with chlorambucil. METHODS: Scintigraphy and 7-day turnover studies were performed in JRA patients with histologically proven (n = 35) or clinically suspected (n = 30) AA amyloidosis, following intravenous injection of 123I and 125I-labeled serum amyloid P component (SAP). Prospective monitoring studies were performed over 2-3 years in 20 patients with amyloidosis. All but 2 amyloidosis patients were treated with chlorambucil. RESULTS: Positive scanning results were obtained in all patients in whom imaging was performed within 12 years of positive biopsy findings of amyloid and in 5 patients with clinically suspected amyloidosis. Negative scanning results with normal SAP metabolism, indicating regression of amyloid, were obtained in 4 patients whose amyloidosis had been in full clinical remission for more than 12 years. Prospective monitoring studies in patients whose JRA-associated inflammatory activity was in remission demonstrated regression of amyloid in 8 patients and no substantial changes in 8 others; however, in 4 further patients with active inflammation, there was accumulation of amyloid. There was a very poor correlation between the amount of amyloid present at a particular site and the resultant organ dysfunction. CONCLUSION: Radiolabeled SAP scintigraphy and turnover studies are useful complementary tools in the diagnosis, screening, and quantitative monitoring of type AA amyloidosis in JRA. The amyloid deposits may progress and/or regress at different rates in different anatomic sites over short periods.     

Intractable diarrhoea associated with secondary amyloidosis in rheumatoid arthritis

OBJECTIVE: To examine the clinical characteristics of intractable diarrhoea associated with secondary amyloidosis in rheumatoid arthritis (RA). METHODS: Of 179 RA patients with biopsy confirmed secondary amyloidosis, 24 cases (23 women and one man) with intractable diarrhoea lasting for more than one month were retrospectively evaluated. RESULTS: The mean (SD) duration of diarrhoea was 87 (64) days. Prodromal symptoms of gastrointestinal dysfunction (n = 21) and impaired peristalsis (n = 16) were observed. Laboratory data showed hypoproteinaemia (4.7 (0.85) g/dl) caused by malabsorption or protein loss and high values of C reactive protein (17.0 (9.3) mg/dl). Recurrence of intractable diarrhoea (n = 4) and transition from intractable diarrhoea to other gastrointestinal problems of amyloidosis (ischaemic colitis (n = 2) and intestinal pseudo-obstruction (n = 4)) were observed. In 19 patients (25 episodes) the duration of intravenous hyperalimentation at remission (18 episodes) was 68 (52) days. Corticosteroid pulse therapy was administered to 10 patients (11 times) and the time elapsed from the end of corticosteroid pulse therapy to the end of diarrhoea was 18 (14) days. One and five year survival rates after the onset of intractable diarrhoea were 73.4% and 38.9%. Seven of 13 patients (54%) had died as a result of infectious diseases. CONCLUSION: Intractable diarrhoea associated with secondary amyloidosis in RA is a serious clinical entity and the prognosis is poor. Although it is assumed that intravenous hyperalimentation treatment and corticosteroid pulse therapy are favourable regimens for intractable diarrhoea, the patients should be monitored for possible infectious complications.     

Inflammatory amyloidosis

Inflammatory amyloidosis consists of AA protein. In developed countries, its predominant causes are chronic inflammatory rheumatism (rheumatoid arthritis, chronic juvenile arthritis, spondylarthropathy, etc.). More rare are other chronic inflammatory disorders (Crohn's disease, ulcerative colitis, Whipple's disease, etc.), hemopathies and neoplasia. In developing countries, infectious causes are the most common (tuberculosis, leprosy, chronic bacterial suppuration). Other infectious diseases complicated with amyloidosis are less common (bronchial dilatation, mucoyiscidosis, heroin injection-related skin suppuration). In chronic infection, amyloidosis is observed a mean of 10 years after the beginning of the triggering disorder and is mainly localised in the kidney, the liver and the gastrointestinal tract. The course is most often slow and prolonged survival has been reported.     

Amyloidosis secondary to rheumatoid arthritis associated with plexiform change in bilateral temporal lobes

A 70-year-old woman with rheumatoid arthritis (RA) and secondary amyloidosis presented repeated consciousness loss. The pathological findings at autopsy revealed multi-organic deposits of amyloid A-protein and so-called 'plexiform change' of blood vessels in bilateral temporal lobes. The arterial plexiform change, which is found in the lung specimen of primary pulmonary hypertension, might be a new pathological cerebrovascular change associated with RA.     

Do minocycline and other tetracyclines have a place in rheumatology?

Tetracyclines are a family of antimicrobials with activity against a broad range of organisms including those that develop intracellularly. Links have been reported between some infections and some inflammatory joint diseases, with the most notable example involving mycoplasmas and rheumatoid arthritis. Reactive arthritides are known to be triggered by organisms found in the gastrointestinal or genitourinary tract, and antigenic material from these organisms has recently been demonstrated in synovial tissue from patients with reactive arthritis. These facts led to the hypothesis that tetracyclines may be useful in rheumatoid arthritis and reactive arthritis. Two controlled studies found that minocycline benefited rheumatoid arthritis patients when it was given either as an adjunct to another second-line treatment or as the only slow-acting drug. Lymecycline has been found to expedite recovery from reactive arthritis due to Chlamydia trachomatis, and tetracycline to decrease the incidence of reactive arthritis due to sexually-transmitted diseases. The safety profiles of these treatments were acceptable in all available studies but require further investigation during long-term administration. The benefits may be related to the immunomodulating effects of tetracyclines and/or to their ability to inhibit metalloproteases such as collagenases. Whether tetracycline therapy influences the course of radiologic lesions in rheumatoid arthritis remains unknown. However, minocycline therapy has given sufficient proof of its efficacy to make it an attractive alternative in rheumatoid arthritis.     

Effect of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the induction of low-density lipoprotein receptor in HepG2 cells

Twelve patients with rheumatoid arthritis treated for at least 12 months with methotrexate and 11 matched rheumatoid arthritis controls underwent a standard d-xylose absorption test. No patients had any pre-existing clinical of biochemical evidence of malabsorption. No significant difference was observed in the 1 hour plasma d-xylose estimation between methotrexate treated patients and controls. The 2 to 5 hour urinary excretion ratio, however, was significantly lower in the methotrexate-treated group compared with controls indicating a minor degree of malabsorption. Six of the methotrexate treated patients and 5 of the controls underwent endoscopic duodenal biopsy but neither group demonstrated any significant histological changes. In conclusion, methotrexate therapy in patients with rheumatoid arthritis produces mild intestinal malabsorption.     

Contact allergy to gold and gold therapy in patients with rheumatoid arthritis

Patients with rheumatoid arthritis were investigated for contact allergy to gold in connection with treatment with gold preparations. There were 57 patients with rheumatoid arthritis previously treated with gold, with or without cutaneous side-effects, as well as 20 patients intended for such treatment; all were exposed to patch and intradermal tests with gold sodium thiosulfate, gold sodium thiomalate and auranofin. Contact allergy to gold was demonstrated in 8 out of 77 patients (10.4%). In the retrospective material, gold allergy was found in 1.8%, in the prospective material in 35.0%. Contact allergy to gold is very frequent among patients with rheumatoid arthritis before gold therapy. In order to avoid early hypersensitivity reactions skin tests should be carried out before gold therapy is instituted.     

Arterial haemorrhage following instillation of silver nitrate in chyluria: treatment by coil embolization

We studied whether the low serum C-reactive protein (S-CRP) level in patients with inflammatory arthritis and proteinuria was due to the loss of CRP into urine. In 19 patients with secondary amyloidosis (14 with rheumatoid arthritis and five with juvenile chronic arthritis), S-CRP was measured with both immunoturbidimetric and radioimmunoassays. The concentration of urinary CRP was measured with a double-antibody radioimmunoassay. One patient with the most extensive proteinuria (12 g/24 h) excreted CRP at 14 mg/24 h, while in 18 of 19 patients only negligible, if any, amounts of CRP were found in 24-h urine samples. Proteinuria of < 8 g/24 h did not reduce the S-CRP level. Proteinuria exceeding this level may result in increased excretion of CRP into urine and consequently may result in a reduced S-CRP level.     

A case of interstitial pneumonia in polymyositis difficult to distinguish from gold pneumonitis

Rheumatoid arthritis was diagnosed in a 48-year-old woman. She received a gold compound, and 4 weeks after the start of that therapy, interstitial pneumonia appeared. Findings from a muscle biopsy, and high serum CPK and LDH levels indicated that she suffered from polymyositis rather than rheumatoid arthritis. The result of a drug lymphocyte stimulation test (DLST) for the gold compound was more than 200%. Because the usefulness of the DLST for the gold compound in the diagnosis of gold pneumonitis is not thoroughly established, the DLST was also done in patients with rheumatoid arthritis who were receiving the gold compound without side effects, and in normal subjects. Many of the rheumatoid arthritis patients and some of the normal subjects had a positive response to the gold compound. Therefore a positive response on the DLST for the gold compound does not always support the diagnosis of gold pneumonitis.     

A case of membranous glomerulonephritis associated with gastric cancer

We describe a patient with gastric cancer and membranous glomerulonephritis (MGN). The patient, a 61-year-old male, was admitted to our Hospital in May, 1996, because of proteinuria and hyperlipidemia persisting for a year. Laboratory examination filled the criteria of nephrotic syndrome and renal biopsy revealed MGN of stage II. Prednisolone therapy (40 mg/day p.o.) was started, followed by a gradual decrease in proteinuria from 4.5 g/day to 0.1 g/day. Endoscopic examination was performed because of stomach-ache revealed advanced gastric cancer of Borrmann 4. Desiring for a conservative therapy, he was discharged and moved to a hospice. In literature review, MGN is the most frequent lesion among various glomerular diseases associated with malignancy, such as the lung, stomach, and colon, particularly at an elderly ages, and sometimes antedates the detection of malignancy, as in the present case. In several cases with MGN, immune-complexes composed of tumor antigens, such as carcino-embryonic antigen, and antibodies have been reported to deposit in basement membrane of glomeruli, causing MGN. In the renal and gastric cancer tissues of the present case, the presence of three novel tumor-associated antigens, Span-1, Thomsen-Friedenreich antigen (T antigen) and F1 alpha antigen, was examined, using a immuno-peroxidase method. Although none of these three antigens were immuno-stained in the renal tissue, clinical course and literature review suggest that MGN in this patient seems to be associated with gastric cancer, which may have produced MGN-causing tumor antigens other than the three antigens. It should be emphasized that malignancy should be carefully and routinely examined in patients with MGN, particularly at elderly ages.     

Incidence of acral nodulosis with long-term methotrexate therapy in patients with inflammatory rheumatic diseases

The significance of acral nodulosis under methotrexate therapy is still controversial. Among patients with rheumatoid arthritis and methotrexate therapy this manifestation could be observed in 8/163 (5%). All cases were seropositive and already treated with other LAAD. Patients with other inflammatory rheumatic diseases under methotrexate therapy (n = 83) did not develop this nodulosis. The acral nodulosis is interpreted as a typical side-effect of methotrexate only in patients with rheumatoid arthritis. Histopathologically, these nodules do not differ from the typical rheumatoid nodule.     

Rheumatoid nodule diagnosed by thoracoscopy using flexible fiberoptic bronchoscope

A 51-year-old man had been treated at a nearby hospital since 1993 for rheumatoid arthritis. Right pectoralgia developed in December 1994, and the patient consulted a nearby hospital, which detected right pleural effusion retention was pointed out on chest x-ray films. The patient was referred and admitted to our hospital. Rheumatic pleurisy was suspected because of a high serum rheumatoid factor(RF)level and high RF and high rheumatoid arthritis hemagglutination levels in the pleural effusion. However, due to a high adenosine deaminase level in the pleural effusion tuberculous pleurisy could not be ruled out. After drainage through a trocar catheter, the thoracic cavity was examined by thoracoscopy through the site of catheter insertion. As a result, sporadic bluish white nodular lesions were observed on the pleura. Granuloma formations presenting a palisade arrangement of giant cells were also observed, and pathologically diagnosed as rheumatoid nodules, thus providing the basis for a diagnosis of rheumatic pleurisy. Treatment with an increased dose of prednisolone achieved a rapid remission of the pleural effusion. Our experience underscored the usefulness of thoracoscopy as a means diagnosing of rheumatic pleurisy.     

Modern medical management of pulmonary tuberculosis

Varicoid was administered to 170 patients with rheumatoid arthritis, to 11 patients with a diagnostically uncertain monarthritis, to 12 patients with exudative gonarthrosis and also to 4 patients with lupus erythematodes visceralis. A total of 262 joints were treated. The short-term results, which were evaluated 4 weeks after the administration of Varicocid, revealed improvement is 95% of the patients. After 12 months, 46% of the patients were found to be free from symptoms within the area of the treated joint, and 33% of the patients showed a considerable improvement. An objectively evident improvement was found in 35 out of 40 patients with rheumatoid arthritis followed up over a period of 3 years. Comparable results after treatment with Varicocid were also obtained in patients suffering from any one of the above-mentioned rheumatic diseases. A new inflammation activity/function index for the evaluation of the local joint therapy has been used. The first investigations both of function and of morphology of the synovial membrane treated with Varicocid are reported. In our opinion, chemical synovectomy with Varicocid fills a gap in the therapy of the rheumatoid arthritis. The essential value of this type of therapy is the absence of toxicity, a temporary increase in local reactions only, and also a continuous improvement, especially in early cases.     

Rapid development of severe osteoarthritis associated with osteoid osteoma in a young girl

A 52-year-old woman with a seven-year history of rheumatoid arthritis (RA) was transferred to our department with chronic renal failure to undergo hemodialysis. She had been treated with prednisolone for a long time, and had renal amyloidosis secondary to RA. During her hospitalization, a left pleural effusion developed. Pleural fluid cultured positive for Cryptococcus neoformans (CN), and the CN antigen was detected in both pleural fluid and serum. Chest computerized tomography revealed an infiltrate shadow in the left lower lung field suggestive of CN infection. This was successfully treated with anti-fungal agents. Pleural effusion is an unusual manifestation of pulmonary cryptococcosis. We should consider a diagnosis of CN infection when pleural effusion is observed in compromised patients such as those receiving a long-term corticosteroid treatment.     

Hypertransaminemia and methotrexate: not always a toxic effect?

Serial measurement of liver enzymes is useful to detect liver toxicity due to methotrexate in patients with rheumatoid arthritis or other rheumatic diseases. We have reviewed retrospectively 141 adult patients treated with methotrexate from 1988 to 1991. The more common diagnoses included rheumatoid arthritis (120 cases) and psoriatic arthritis (12 cases). In periodic studies carried our every 2-3 months, a transient increase in transaminase values associated with methotrexate in 13 patients (9.2%) was observed. Two patients developed a viral infection during therapy, one due to cytomegalovirus and the other due to the Epstein-Barr virus. Both patients had a favorable outcome once methotrexate was withdrawn.