Effect of Avemar--a fermented wheat germ extract--on rheumatoid arthritis. Preliminary data.

OBJECTIVE: To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA). METHODS: Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used. RESULTS: At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed. CONCLUSION: Supplementation of standard therapies with a continuous administration of Avemar is beneficial for RA patients.

Histochemical and immunohistochemical differential diagnosis of amyloidosis--a brief illustrated essay and personal experience with Romhányi's method.

The histochemical and immunohistochemical differential diagnosis of amyloidosis in surgical pathology in a referral center is presented. Different forms of amyloidosis are considered e.g. systemic generalized amyloidosis: secondary (AA), primary (AL), senile, hemodialysis-associated, hereditary and organ (tissue)-limited (localized) amyloidosis: cerebral, dystrophic (age-related, so-called "senile"), endocrine-related, localized to tumours, focal (concentrated secretion), and isolated plasma cell (solitary plasmacytoma, B-cell) dyscrasia related amyloidosis. The amyloid deposits were identified and characterized histochemically by Congo red staining after performate pre-treatment at 20 degrees C for 1, 3, 5, 10, 15, 20 or 25 sec, and with oxidation induced proteolysis by trypsin digestion at 20 degrees C for 5, 10, or 30 sec, 1, 2, 3, 4, 5, 6 or 10 min and covered with gum-arabic according to Romhányi, and confirmed by streptavidin-biotin-complex/horseradish peroxidase immunohistochemical reactions. The "sensitivity" or "resistance" to pre-treatment of amyloid deposits depends on the type of amyloid, and the length of pre-treatment. Secondary (AA) amyloid is sensitive to KMnO4 oxidation, followed by trypsin digestion (for 1 min), and its green birefringence under polarized light disappears, while primary (AL) (for 1-5 min), senile (for 1-10 min), and most forms of organ (tissue)-limited (localized) amyloid (for 1-10 min) are resistant. Performate pre-treatment is followed by pronounced congophilia. Secondary (AA) is sensitive to performate pre-treatment (for 1 sec), while primary (AL) amyloid (for 1-20 sec), senile (for 1-25 sec), and most forms of organ (tissue)-limited (localized, isolated) amyloid deposits (for 1-25 sec) are resistant, and are constantly positively birefringent. Early identification and differentiation of amyloid deposits is important for the prognosis and for the choice of therapy. The authors conclude that the presented classical histochemical methods are useful as first line screens for the histological identification of amyloidosis.

[Caudal epidural injection in the management of lumbosacral nerve pain syndromes]. / Caudalis epiduralis injekció az akut lumbosacralis gyöki fájdalomszindrómák kezelésében.

The effect of epidural steroid injections was assessed in 39 patients with lumbar nerve root compression syndromes in a double-blind controlled trial, the patients were allocated at random to 3 groups. In group A (n = 13) the patients received a caudal epidural injection of 1 ml (7 mg) bethametason (Diprophos) in 10 ml normal saline and 20 ml local anesthetic (Lignocaine 1%). The second group B (n = 13) received a caudal epidural injection of 20 ml local anaesthetic (Lignocaine 1%) and 10 ml normal saline. The third group C (n = 13) received a superficial injection of 1 ml (7 mg) bethametason around of the sacral hiatus. All injections were performed by the same experienced anaesthesiologist. An independent physician, who was not aware which type of injection had been given, carried out the clinical measurements and the evaluation. Taking of analgesic drug Tramadol was permitted. The symptoms were assessed by visual analogue scale (VAS 100 mm), lumbar flexion (Schober and finger-floor distance), the angle of raised leg sign (RLS degrees), and by complete neurological examination, the investigation was made 5 times (1 hour, 24 hours, 48 hours, 1 week, and 4 weeks after epidural injections). The results between 0-1 week and 0-4 week were statistically analysed by Student-, Wilcoxon-, and Mann-Whitney test and analysis of variance (ANOVA). The mean VAS values decreased in time in all patient groups. There was no difference between the three treatment groups either after one or after 4 weeks by ANOVA. The mobility of the lumbar spine improved in all patient groups, but there was no significant difference between the three treatment groups. The raised led sign--values improved in all patient groups. There was a significant difference between the three treatment groups by ANOVA after one week, due to the difference between group A and C. After four weeks there was no significant difference. No major complications or side effects were seen in our trial. The raised leg sign due to epidural steroid injection showed better results in comparison to steroid injection around of the sacral hiatus were seen.

[Tumors in rheumatoid arthritis]. / Daganatos megbetegedések rheumatoid arthritisben.

Benign (bTu) and malignant tumours (mTu) were studied in a randomised autopsy material of 161 patients with rheumatoid arthritis (RA). The tissue specimens were fixed in 8% formaldehyde solution at pH 7.6 and embedded in paraffin. The tumours were diagnosed histologically and confirmed by immunohistochemical methods. Five benign (3.1%), and thirteen malignant tumours (8.1%) found observed in 18 (11.2%) of 161 cases. There was no significant difference between laboratory parameters of patients with malignant tumours and without tumours. One benign (0.62%) and seven malignant (4.35%) tumours led to death in 8 (4.97%) of 18 cases altogether. Neoplasms were detected clinically in 8 of 18 cases (44.4 rel%). None of tumorous patients received immunosuppressive treatment and only five had gold (Tauredon) therapy. Paraneoplastic syndromes with rheumatoid complaints may be excluded by the onset and duration of RA and tumours. Benign neurogenic tumours and malignant bronchioloalveolar carcinoma were frequently associated with RA not treated by immunosuppressive drugs. Our data do not support the assumption of a high risk of malignant lymphomas associated with RA treated with immunosuppressive therapy.

[Vasculitis in rheumatoid arthritis]. / Vasculitis rheumatoid arthritisben.

The frequency and histopathological characteristics of systemic vasculitis were studied in the autopsy material of 161 patients with rheumatoid arthritis. Systemic vasculitis was observed in 36 case (22.4%). In percentage of all cases with systemic vasculitis, the most frequently involved organs were the heart (66.7%), skeletal muscles (54.8%), and peripheral nerves (52%). The skin was involved only in about one third of 36 cases (36%). In most cases the arterioles and the small arteries were affected by vasculitis. Three types of vasculitis (non specific, fibrinoid necrotic, granulomatous) could be observed simultaneously in different vessels or combined in the same vessel. Different stages of inflammation could be found simultaneously, reflecting the relapsing nature of vasculitis. The frequency, the severity, and the recurrence of vasculitis are different aspects of the same phenomenon running usually parallel to each other in different organs and on different vessels. Vasculitis lead to local ischaemia and regressive changes depend on the number and size of the involved vessels. Systemic vasculitis led to death in 19 of 36 cases. Vasculitis was detected clinically in 7 of 36 cases. Exitus lethalis depend on the localization of the involved vessels. Vasculitis in the heart and brain are more life threatening, than that of localized to the skin.

[Generalized septic infections in rheumatoid arthritis. Study of autopsy material]. / Generalisierte septische Infektionen bei chronischer Polyarthritis. Eine Untersuchung am Autopsiegut.

In the randomized autopsy material of 161 patients with rheumatoid arthritis (RA), a letal, generalized septic infection (GSI) was observed in 22 cases (13.66%). The GSI was accompanied by a pyarthros in 12 (7.45%) and no pyarthros in 10 (6.21%) cases. The clinical parameters of 22 septic RA patients were compared with 139 age and sex matched RA patients without GSI. The average age of septic patients decreased (p < 0.02), with low serum electrophoretic b-globulin level (p < 0.04), and high Waaler-Rose (p < 0.02) and Latex level (p < 0.004). The clinical parameters of 22 septic patients were compared with 76 age and sex matched RA patients without sepsis, vasculitis, or generalized secondary amyloidosis (GSA), and/or miliary epitheloid granulomas of tuberculous type (mT). The differences between the two groups of patients were the same, with a statistically more pronounced age difference (p < 0.005). 29 out of 161 patients (18.01 %) suffered from a clinically manifest diabetes mellitus (in 6 patients accompanied by sepsis), and 11 (6.83 %) from a clinically latent diabetes mellitus (in 2 patients accompanied by sepsis). There was no significant relationship between sepsis and manifest diabetes mellitus. The controlled and treated diabetes mellitus does not influence the frequency of lethal sepsis. Significant correlations were found between sepsis and latent diabetes mellitus (based on the histological detection of amyloid deposition localized to the islets of Langerhans (p < 0.02). 34 out of 161 patients (21.12%) suffered from a generalized secondary amyloidosis (in 3 patients accompanied by sepsis). There was no significant relationship between sepsis and generalized secondary amyloidosis. The thickness of adrenal cortex represents the effect of steroid therapy. Critical random check, using the Mann-Whitney tests, supports significance relationship between the adrenal cortex atrophy and fatal sepsis (p < 0.010). The follicular lymphoid depletion in the spleen represents the effect of immunosuppressive therapy. The size of lympho-follicles decreased significantly in sepsis (p < 0.004). The long term corticosteroid therapy and immunosuppressive represent a potential danger for sepsis.

[Causes of death as well as complications in rheumatoid arthritis]. / Halálokok, szövödmények rheumatoid arthritisben.

The frequency of basic diseases, complications, causes of death and associated illnesses were studied on non selected autopsy material of 161 patients with rheumatoid arthritis died at the National Institute of Rheumatology in 1970-1992. The authors determined the incidence of severe complications such as systemic vasculitis, generalized secondary amyloidosis, generalized septic infection and miliary epithelioid granulomatosis (probably miliary tuberculosis). In 122 cases (75.8%) the RA, while in the remaining 39 (24.2%) cases other basic disease was the underlying cause of death. Vasculitis was observed in 36 cases (22.4%), amyloidosis in 34 (21.1%), sepsis in 22 (13.7%), and miliary tuberculosis in 6 (3.7%) out of 161 RA patients. Vasculitis led to death in 19 (11.8%), amyloidosis in 17 (10.6%), sepsis in 22 (13.7%) cases. However, none of the miliary tuberculosis was direct cause of death. In 76 cases (47.2%) rheumatoid arthritis was not complicated by vasculitis, amyloidosis, sepsis or military tuberculosis and in 85 cases (52.8%) one or more of these complications existed in the necropsy material of 161 RA patients. In 74 patients (46%) only one complication and in 11 (6.8%) more than one from the mentioned complication existed simultaneously in the same patients. Vasculitis was detected clinically in 7 patients (relative frequency: 19.4%), amyloidosis in 8 (relative frequency: 23.5%), sepsis in 10 (relative frequency: 45.4%), however none of the 6 mT was detected clinically. Out of 98 complications in 85 Rheumatoid patients only 25 were recognized clinically (25.5%).

[Generalized secondary amyloidosis in rheumatoid arthritis]. / Generalizált secunder amyloidosis rheumatoid arthritisben.

Generalized (systemic) secondary amyloidosis was a post mortem finding recorded in 28 patients (25.2%) by amyloid specific Congored staining according to Romhányi, from 111 randomized autopsy cases with rheumatoid arthritis. Amyloidosis was present most frequently in the gastro-intestinal tract, the heart, kidney, thyroid gland, spleen and in the suprarenal glands. The quantity of amyloid deposits is usually the highest in the organs that are most frequently have deposits. The amyloidosis is a progressive cumulative process. The conclusion is that the organs where there are frequently high quantities of amyloid is where the deposits begin and where there are infrequently any deposits or low quantities is where the deposits develop later. Biopsy of the most frequently involved organs are suggested for early diagnosis of amyloidosis. Comparing the laboratory parameters (at the last hospitalisation), the amyloidotic patients were anaemic, with low haemoglobin level (p < 0.05), the renal function significantly decreased, the carbamid (p < 0.001), and kreatinin level high (p < 0.05), with frequent proteinuria (p < 0.0001).

[Disease-modifying factors in chronic polyarthritis. Correlations amongsystemic vasculitis, secondary amyloidosis, septic infections and occurrence of miliary epitheloid-cell granuloma. A review of autopsies]. / Krankheitsmodifizierende Faktoren bei chronischer Polyarthritis. Uber Zusammenhänge zwischen generalisierter Vaskulitis, sekundärer Amyloidose, septischen Infektionen und Auftreten von miliaren epitheloidzelligen Granulomen. Eine Untersuchung am Autopsiegut.

The following findings were obtained from autopsies performed on 169 deceased with chronic polyarthritis (CP): systemic vasculitis in 26 cases (15.4%), systemic secondary amyloidosis in 32 cases (18.9%), sepsis in 13 cases (7.7%) and miliary epithelioid-cell granulomatosis (probably tuberculosis) in six cases (3.6%). Vasculitis was combined with amyloidosis in five patients, with sepsis in two and with miliary epithelioid-cell granulomatosis in four. Critical random check, using the Mann-Whitney test, did not support significance of relationship between vasculitis and amyloidosis or fatal sepsis, whereas significant correlations were found to exist in CP cases between vasculitis and miliary epithelioid-cell granulomatosis (P < 0.005). The latter had no effect on the severity of vasculitis, but the incidence of the granulomatous type of vasculitis was higher with significance (P < 0.02). The conclusion is that biopsy evidence of granulomatous vasculitis in CP patients should be followed by systematic clinical search for miliary tuberculosis because of above-average incidence of that combination.

Cardiac changes in rheumatoid arthritis.

We reviewed the autopsy material of 169 patients with rheumatoid arthritis (RA) and studied the cardiac changes is these patients. Systemic vasculitis was observed in 26 cases (15.38%) among 169 patients with RA. In 17 cases (10%) we found vasculitis of the subepicardial and/or intramural coronary vessels. Coronary arteritis or arteriolotis has led to multifocal small, and/or large myocardial infarctions in 10 cases (5.9%) and was the cause of progressive cardiac insufficiency, the direct cause of death. Multifocal circumscribed myocardial infarction reported in rheumatoid disease. In 8 cases rheumatoid nodules were found in the myocardium, 3 of them related to vasculitis. We suggest that rheumatoid nodules are the most severe form of necrotizing granulomatous vasculitis. Pathognomic nodular rheumatoid pericarditis was seen in 3 cases and diffuse rheumatoid pericarditis in another case. Pathognomic nodular valvulitis was found in 7 cases. Rheumatoid nodules localized to the epi-, myo-, or endocardium were observed on 9 patients. Generalized secondary amyloidosis was observed in 32 (18.93%) of the 169 patients with RA. Secondary amyloidosis was prevalent in the heart in 29 of 32 cases (relative frequency: 90.62%).

Generalized secondary amyloidosis in rheumatoid arthritis.

The autopsy material of 215 RA patients was studied to determine 1) the frequency of generalized secondary amyloidosis (GSA), 2) the frequency and extent of amyloid deposits in various organs, 3) the chronological succession of amyloid deposition in various organs. The tissue specimens were fixed in 8% formaldehyde solution and embedded in paraffin. Serial sections were cut and stained with HE and Congo-red according to Romhányi, without alcoholic differentiation. The average amount of amyloid deposition in various organs was determined on a 0 to 4 plus scale. Thirty-seven cases were found to contain stainable amyloid (17.2%). The frequency and degree of amyloid deposition in different organs of RA cases with GSA are summarized in the following table. [table: see text] The frequency and extent of amyloid deposits in various organs may be linked to the ratio of cardiac output distributed over a different tissue mass. In conclusion, the tissues and organs often showing high quantities of amyloid are the sites where the deposits begin. Where deposits are infrequent or of low quantity deposits develop later. Amyloid deposits early in the wall of blood vessels, first of all within the GI tract, heart, kidneys, thyroid gland, spleen and the adrenal glands.

[Heart alterations in chronic polyarthritis]. / Herzveränderungen bei chronischer Polyarthritis.

Described in this paper are pathomorphological alterations to the heart postmortem recorded from 100 deceased with rheumatoid arthritis. Vasculitis of subepicardial or intramural rami of coronary arteries was recorded from twelve cases and had caused multiple myocardial necrosis in ten of these. These developments had led to progressive cardiac insufficiency which actually then was the direct cause of death. Formal pathogenesis of vasculitis-related multifocal myocardial necrosis in concomitance with rheumatoid arthritis had never been described in the literature before, although such reference would have been justified for the clinical consequences for which it deserves to be emphasised as a nosological entity in its own right. Isolated rheumatic nodes were detected in the myocardium of five of the decreased and could be attributed to rheumatic arteritis in two cases. Those myocardial rheumatic nodes, according to the author's view, represent the severest form of necrotising rheumatic vasculitis. Pathognomonic pericarditis was found in four cases (2 pericarditis nodularis and 2 pericarditis rheumatica). Pathognomonic nodular valvulitis was identified in another four cases. Systemic secondary amyloidoses were found to be present in 24 of the above 100 deceased with chronic polyarthritis. The heart was involved in 23 of these 24 cases (95.8%).

Changes of the lung in rheumatoid arthritis--rheumatoid pneumonia. A clinicopathological study.

The frequency and patho-histological characteristics of pulmonary changes were studied on the autopsy material of 100 patients with rheumatoid arthritis (RA). The formal pathogenesis and different stages of vasculitis, rheumatoid nodule, interstitial pneumonia, rheumatoid pleuritis, obliterative bronchiolitis, amyloidosis and the so-called rheumatoid pneumonia in the lungs is discussed. The rheumatoid pneumonia is a disseminating inflammatory lobular-sublobular process, not described previously. The frequency of rheumatoid pneumonia was 4%. The rheumatoid pneumonia is characterized by the necrotic vasculitis, fibrinoid necrosis or thrombovasculitis of the pulmonary and bronchial arterioles, and of small arteries. Because of the diminished blood supply distal to the vascular changes inflammatory foci may develop, more or less respecting the anatomic borders of pulmonary tissue. The lobular-sublobular inflammation is basically of non haemorrhagic character. Because of the recurrent nature of vasculitis, foci of inflammation in different stages can be observed in the lungs simultaneously side by side. Clinically the rheumatoid pneumonia was accompanied by severe RA, according to the frequency and severity of acute exacerbations. In all 4 cases of rheumatoid pneumonia the pulmonary process had been proven clinically and radiologically. Rheumatoid pneumonia occurred subsequent to recurrent arthritis following steroid withdrawal, and it was resistant to antibiotics.

[Pancreatitis in rheumatoid arthritis found in autopsy material]. / Hasnyálmirigy gyulladás rheumatoid arthritisben, autopsziás anyagon.

Authors have studied in autopsy samples of 80 patients having suffered from rheumatoid arthritis the incidence and types of pancreatitis. There were 6 acute, 4 chronic-recurrent and 11 chronic severe or moderately severe pancreatitis observed. In the ethiology of pancreatites the ductal origin, cholelithiasis and uraemia were not found to be of exclusively significance. In 3 cases a pancreatitis was found accompanied by vasculitis and a typical histological pattern characterized by the vasculitis-thrombovasculitis of arterioles and small arteries with simultaneously occurring necrotic foci. In one case a pancreatitis due to severe amyloidosis could be verified. Authors draw attention to the frequent occurrence of pancreatitis in patients suffering from rheumatoid arthritis and the difficulties of a clinical diagnosis.