Immunohistology of rheumatoid nodules and rheumatoid synovium.

The immunohistological features of rheumatoid nodules and rheumatoid synovium were examined using monoclonal and polyclonal antibodies raised against macrophages, HLA-DR, leucocyte common antigen, and immunoglobulin components. The palisading cells surrounding the necrotic centre of the rheumatoid nodule were shown to be HLA-DR positive leucocytes, mostly histiocytes. The inflammatory infiltrate associated with rheumatoid nodules showed many immunohistochemical similarities to that of rheumatoid synovium, including a preponderance of IgG positive plasma cells, and a similar number and microanatomical pattern of distribution of HLA-DR positive cells. The significance of these findings for the cellular immunopathology and aetiology of the rheumatoid lesion is discussed.     

Cell death by apoptosis is a feature of the rheumatoid nodule

OBJECTIVE: To examine the site and extent of apoptosis in the rheumatoid nodule and to determine whether this process make a significant contribution to the control of inflammation in the rheumatoid nodule as in other granulomas. METHODS: Nine nodules and seven synovial membranes were examined by terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) in situ and a subset was further examined by DNA electrophoresis. The phenotype of apoptotic cells was identified using monoclonal antibodies and immunohistology. RESULTS: Apoptosis occurred in all zones of the nodule and, except in one case, was not focused adjacent to the necrotic centre. Apoptosis occurred in 3.5 (4.5)% (mean (SD)) of cells in the nodule and 3.6 (3.1)% of cells in synovial membranes. Apoptosis was more common in nodule T cells (4.1 (2.9)%) than fibroblasts (1.0 (1.4)%), p = 0.01. Among macrophages 3.2 (4.7)% were apoptotic. Banding of DNA consistent with apoptosis was seen in two of three nodules examined. CONCLUSION: Apoptosis occurs at a low level in the nodule, similar to the synovial membrane. The results suggest that two modes of cell death occur in the nodule: apoptosis, which occurs throughout the nodule; and necrosis, which is concentrated near the necrotic centre. Apoptosis was more common in infiltrating inflammatory cells than in resident fibroblasts. These results are consistent with the proposal that apoptosis of infiltrating inflammatory cells is important in controlling accumulation of cells in the rheumatoid nodule as has been established in experimental granulomas.     

Tumour necrosis factor alpha independent disease mechanisms in rheumatoid arthritis: a histopathological study on the effect of infliximab on rheumatoid nodules

BACKGROUND: It has been suggested that the immunopathology of rheumatoid nodules parallels that of inflamed synovium in rheumatoid arthritis (RA). OBJECTIVE: To analyse the effect of infliximab on the immunopathology of rheumatoid nodules in order to provide new insights into the relationship between synovial inflammation and rheumatoid nodules. MATERIALS AND METHODS: Nodules were present at baseline in six patients with RA and after infliximab treatment in five patients, including paired nodules before and after treatment in three patients. In one patient, the nodule appeared during treatment. Paraffin sections were used for histological analysis. Frozen sections were stained by immunohistochemistry for cellular markers (CD3, CD4, CD8, CD16, CD20, CD68), blood vessels (CD146, vWF, alphavbeta3), and adhesion molecules (E-selectin, VCAM-1, ICAM-1). RESULTS: No manifest immunopathological differences were found between the nodules before and after infliximab treatment. All nodules depicted the classical structure with a central necrotic zone, surrounding the palisade layer, and an outer connective tissue zone. Immunohistochemistry showed the presence of CD68+ and CD16+ macrophages in the palisade and the connective tissue zone, as well as a small number of CD3+, CD4+ T lymphocytes in the perivascular areas. Small vessels were seen in the connective tissue and were sometimes positive for the neovascularisation marker alphavbeta3. They expressed no VCAM-1, E-selectin weakly, but ICAM-1 strongly. ICAM-1 was also strongly expressed on palisade cells. CONCLUSIONS: Despite an improvement of articular symptoms, infliximab treatment had no distinct effect on the histopathology of rheumatoid nodules, suggesting that different pathogenetic mechanisms mediate the two disease manifestations in RA.     

Rheumatoid nodulosis. Sporadic and familial diseases.

Two patients are described with longstanding, multiple, subcutaneous nodules with the histopathological features of rheumatoid nodules. Neither patient had any clinical evidence of rheumatic disease. One patient had a family history of smiliar nodules transmitted as an autosomal dominant trait. Leukocyte function studies failed to reveal any defect to account for the nodule formation.     

Benign rheumatoid nodules in a woman with chronic lymphocytic leukaemia and borderline lepromatous leprosy.

OBJECTIVES--To report benign rheumatoid nodules in a woman with chronic lymphocytic leukaemia and borderline lepromatous leprosy and to summarise the features of the patients with adult onset benign rheumatoid nodules. METHODS--A 66 year old woman with chronic lymphocytic leukaemia and borderline lepromatous leprosy who presented with subcutaneous elbow nodules, which were at first suspected to represent either progression of her haematological disease or leprosy, is described. The clinical characteristics of our patient and previous reports of another 24 subjects with adult onset benign rheumatoid nodules are reviewed. RESULTS--Biopsy of the patient's subcutaneous lesion disclosed the histopathology of a rheumatoid nodule; serological and clinical evaluations for rheumatoid arthritis and other rheumatoid nodule associated systemic diseases were negative. Adult onset benign rheumatoid nodules are clinically and histologically identical to those found in patients with rheumatoid arthritis. They often appeared in women during their 20s, frequently resolved spontaneously or were adequately treated by excision, and recurred in about one third of patients. The lesions were located in the ocular adnexa in 60% of patients. The most common lesional sites in patients with non-ocular benign rheumatoid nodules were the elbows, feet, and knees. None of these patients subsequently developed rheumatoid arthritis or other rheumatoid nodule associated diseases during follow up periods of as long as 20 years. CONCLUSION--The appearance of subcutaneous nodules is often the harbinger of an associated systemic disorder. Although benign rheumatoid nodules occur infrequently in adults, they should be considered in the differential diagnosis of new nodular lesions.     

Multiple intrapulmonary rheumatoid nodules]

A 66-year-old woman who had been treated at a nearby hospital since 1977 for rheumatoid arthritis complained of cough. Chest X-ray films disclosed multiple nodular shadows with cavitation in the fields of both lungs. The patient was admitted to our hospital and a thoracoscopic lung biopsy was performed. Histologically, the nodule consisted of necrotizing granuloma, indicating a necrobiotic nodule. Rheumatoid nodule was diagnosed because the patient exhibited rheumatoid arthritis. The chest X-ray shadow disappeared without medication. Rheumatoid nodules without coniosis are uncommon, but should be considered in the differential diagnosis of lung nodular lesions in patients with rheumatoid arthritis.     

Spontaneous regression of a solitary necrotic nodule of the liver

Solitary necrotic nodules of the liver occur rarely. Although these nodules are usually benign, they are surgically removed in most cases because they cannot be differentiated from malignant lesions. To date, the natural history of solitary fibrous nodules remains unclear. We present the case of an incidentally detected hepatic mass (diameter 2 cm) in a 35-year-old man. The hepatic mass was diagnosed as a solitary necrotic nodule by liver biopsy. Follow-up radiologic examination revealed that the solitary necrotic nodule had spontaneously regressed. This is the first report on the natural course history of a solitary necrotic nodule.     

Comparison of phenotype expression by mononuclear phagocytes within subcutaneous gouty tophi and rheumatoid nodules

Summary The mononuclear phagocyte infiltrate which occupies the gout tophus has been compared with that of the subcutaneous rheumatoid nodule. In the gout tophus, macrophage migration appears to be at a relatively low level and effectively terminates once these cells have been recruited into the corona. In the nodule the evidence suggests that both macrophage and granulocyte populations continuously migrate towards, and are progressively incorporated into, the necrotic centres. These observations indicate that chemotactic activity in rheumatoid nodules is at a higher level than in gout tophi, or that the rheumatoid mononuclear phagocyte is more responsive to such stimuli.     

Enlarged solitary necrotic nodule of the liver misinterpreted as a metastatic liver cancer

Solitary necrotic nodule of the liver is a rare nonmalignant lesion of unknown etiology. It is defined as a nodule with a completely necrotic core enclosed by a hyalinized fibrotic capsule containing elastic fiber. We report a 74-year-old woman with a solitary necrotic nodule of the liver that mimicked metastasis from a previous rectal adenocarcinoma. She was referred to us for an asymptomatic liver nodule in segment 8 that had increased in diameter from 5 to 15 mm over the past 8 months. Ultrasonography showed a well-defined, oval, hypoechoic mass, and computed tomography showed a hypodense area without contrast enhancement except for a ring-like enhancement during hepatic arteriography. Magnetic resonance imaging revealed a mass that was hypointense on T1-weighted imaging and slightly hyperintense on T2-weighted imaging. The patient underwent hepatectomy of segment 8. The resected specimen contained an oval nonencapsulated nodule with firm and gritty consistency and a well-defined margin. Histologic findings were compatible with those of solitary necrotic nodule. Clinicians should recognize the existence of this lesion as one of the differential diagnoses of metastatic liver nodule. Solitary necrotic nodules can change size, and when enlarged, differentiation from metastasis is extremely difficult.     

Regression von peripheren und pulmonalen Rheumaknoten unter Rituximab-Therapie

We report on a retrospective study of 16 rheumatoid arthritis (RA) patients with reduction in size of pulmonary and peripheral rheumatoid nodules following treatment with rituximab (RTX). The 8 female and 8 male patients had an average disease duration of 12.2 years, 88 % were anti-CCP positive and 94 % seropositive. Prior treatment included an average of 2.9 DMARD and 1.4 biological therapies. On average 6.1 rheumatoid nodules were found on hands and elbows and 5 patients had pulmonary nodules. In 6 out of 16 patients the nodules disappeared completely, in 2 patients a pulmonary nodule disappeared. In 10 out of 16 patients the size of the nodules decreased by approximately 50%, 1 out of the 16 patients with significant increase in size and number of nodules prior to RTX therapy showed a reduction in size but no new nodules occurred. The regression in size of the nodules occurred 34.2±39.1 weeks following RTX therapy, correlating with 1.3±0.59 RTX infusion cycles. Overall, increases in size or new nodules were reported in none of the patients. One nodule examined histologically following RTX therapy did not show any specific differences. RTX may lead to a marked reduction in size of rheumatoid nodules in RA patients. More studies are necessary to confirm whether this is an RTX-specific effect.     

Nodular pulmonary opacities in patients with rheumatoid arthritis. A diagnostic dilemma

Nodular opacities are a well-known pulmonary manifestation of rheumatoid arthritis (RA), occurring most often in seropositive men who smoke and have subcutaneous nodules. In the past 15 years two cases of lung carcinoma presenting as pulmonary nodules have been reported in patients with rheumatoid disease. We present seven patients with seropositive RA and subcutaneous nodules who had new pulmonary nodule(s) noted on chest roentgenograms. All but one were current smokers. Carcinoma was found in all patients at bronchoscopy or thoracotomy. Four patients had solitary nodules (one was cavitary); the remaining three patients had multiple bilateral nodules that cavitated in one case. All patients had interstitial abnormality (peribronchial/vascular thickening) with basal predominance in three, and there was evidence of pleural thickening/fluid in three patients. These results strongly suggest that histologic proof of presumed rheumatoid pulmonary nodules be obtained.     

X linked agammaglobulinaemia and rheumatoid arthritis

BACKGROUND: Much interest has been shown recently in the pathogenic role of B cells in rheumatoid arthritis (RA) owing to the marked clinical responses to anti-CD20 treatment in RA. CASE REPORT: A patient with X linked agammaglobulinaemia (XLA) presented with an erosive symmetric polyarthritis with histological features of RA, including formation of a destructive pannus. Furthermore, the patient developed subcutaneous nodules that were histologically indistinguishable from rheumatoid nodules. Surprisingly, lymphocytic infiltrates in both the synovium and nodule consisted almost exclusively of CD8+ T cells. DISCUSSION: Although some peculiar B cell subsets have been described in patients with XLA, no B cell subsets could be demonstrated in synovial tissue or the subcutaneous nodule. This case illustrates that classical RA can develop in the absence of mature B cells.     

Complete reversal of rheumatoid nodulosis

A woman first seen in 1978 had a history of seropositive rheumatoid arthritis (RA) of 12 years' duration with attacks of palindromic rheumatism for 3 years. She was treated with D-penicillamine, pyridoxine and hydroxychloroquine and serial measurements of her grip strength and proximal interphalangeal joint circumference were taken. By 1987 all her nodules had resorbed completely. Hydroxychloroquine effects probably helped her improvement. Although spontaneous resorption of a rheumatoid nodule is not a rare event, to the best of our knowledge, this is the first instance of complete resolution of all nodules in a patient with RA with the nodulosis variant.     

Recurrent pneumothorax associated with pulmonary nodules after leflunomide therapy in rheumatoid arthritis: a case report and review of the literature

Rheumatoid arthritis (RA) is a multisystem inflammatory disease characterized by destructive synovitis and systemic extraarticular involvement. One of the most common pulmonary manifestations of RA is rheumatoid nodule. Spontaneous pneumothorax also very rare pulmonary finding and could be associated with pulmonary nodules. Antirheumatic drugs, methotrexate, leflunomide (LEF), infliximab and etanercept, were known as risk factors for developing rheumatoid nodule. However, there was no case report of rheumatoid nodule-associated pneumothorax with the use of LEF. We report, first, herein a case of 46-year-old woman with RA who suffered recurrent spontaneous pneumothorax associated with multiple bilateral subpleural cavitary nodules during treatment with LEF. We reviewed the cases of LEF-related pulmonary nodules developed in patients with RA. Thus, we suggested that pneumothorax can be a rare respiratory fatal complication in patients with RA with pulmonary nodules and LEF can be a rare cause of these manifestations.     

Embolic complications of a mitral valve rheumatoid nodule

We describe a patient with a rheumatoid nodule on the mitral valve who developed embolic phenomena from an overlying thrombus. It is important to recognize that thrombus can develop on intracardiac rheumatoid nodules and that these patients may require anticoagulation.     

Rheumatoid nodules of the lung in a patient with palindromic rheumatism.

We report a case of rheumatoid nodules of the lung seen in a patient with palindromic rheumatism. A 54-year-old man with palindromic rheumatism was admitted for evaluation of three nodules in the right upper lobe on chest roentgenogram. Wedge resection was performed for the purpose of confirmative diagnosis and treatment. Histology of these lung lesions revealed palisaded histiocytic cells surrounding a layer of central necrosis, which were considered to be characteristic findings of rheumatoid nodule. Such a case is extremely rare. To our knowledge, only one other case has been reported before in the literature.     

Rheumatoid disease and bronchogenic carcinoma--case report and review of the literature

We describe a patient with a solitary pulmonary nodule that proved to be a rheumatoid nodule and a coexistent carcinoma. Similar cases from the literature are reviewed. Fine needle aspiration cytologies from such lesions are potentially misleading and must be interpreted cautiously. Pulmonary nodules in patients with rheumatoid arthritis clearly should be approached as possible carcinomas.     

Nodular pulmonary amyloidosis in a patient with rheumatoid arthritis

We describe a 67-year-old white woman with a long-standing active rheumatoid arthritis who refused treatment. Chest roentgenograms performed in 2000 revealed a pulmonary nodule in the mid-left lung. Progression of the nodule was followed annually by computerized tomography (CT). In the last CT in 2002, we observed multiple nodules in both lungs in the absence of lymph gland involvement. The patient was operated by videothoracoscopy to resect one of the pulmonary nodules. Pathological examination of the excised tissue revealed amyloid A-type (AA) amyloidosis. Although pulmonary amyloidosis is rare in patients with systemic AA amyloidosis, we recommend that this possibility be considered when confronted with a patient with these characteristics.     

Pulmonary rheumatoid nodules demonstrating features usually associated with rheumatoid synovial membrane

OBJECTIVES: To describe the unusual immunohistological characteristics of two pulmonary rheumatoid nodules showing ectopic lymphoid follicles and the features normally associated with rheumatoid synovial membrane, and to discuss the implications of this novel observation. METHODS: Two formalin-fixed wax-embedded pulmonary rheumatoid nodules were processed for immunohistology. RESULTS: The central structure of the pulmonary nodules was typical of that uniformly expected in a rheumatoid nodule with central necrosis surrounded by a palisade of macrophages. However, a feature not previously observed in nodules was the presence of lymphoid aggregates containing B lymphocytes and, in some cases, showing characteristic features of lymphoid follicles. CONCLUSIONS: The presence of B lymphocytes and the development of ectopic lymphoid follicles in rheumatoid nodules have not been described previously. It is similar to synovial membrane, and contrasts with the expected structure of subcutaneous nodules where B cells and lymphoid follicles are normally absent. These observations establish that the morphology of rheumatoid nodules can vary in different tissues. They further suggest that the inflammatory process in the nodule and synovial membrane are likely to be similar, and that the characteristics of different tissues may be an important determinant of apparent differences between inflammatory lesions in synovial membrane and extra-articular nodules in rheumatoid arthritis.     

A giant rheumatoid nodule

Subcutaneous rheumatoid nodules occur commonly in advanced cases of rheumatoid arthritis and are the most common extra-articular lesion of this disease. We present a case of a very unusual giant rheumatoid nodule that developed on the lateral side of a knee. The case was devoid of systemic symptoms of arthritis and the lesion was limited to a rheumatoid nodule. The nodule was successfully treated by surgical excision. However, other new nodules developed in her hand. Her clinical course has not been satisfactory.