Collision Lesions of Calcifying Pseudoneoplasm of the Neuraxis and Rheumatoid Nodules: A Case Report With New Pathogenic Insights.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like lesion with unclear pathogenesis. Collision lesions of CAPNONs with neoplasms are occasionally reported. In this article, we report the first case of collision lesions between CAPNON and rheumatoid nodules (RNs) in a patient with systemic lupus erythematosus. The patient was a 51-year-old female who presented with lower back pain and subsequently a lower back mass over 2 years. Spinal magnetic resonance imaging demonstrated a heterogeneous, partially calcified mass centered in the L3-4 paravertebral regions. A biopsy of the mass was diagnostic of CAPNON. As the mass grew over the following 5 months, it was resected en bloc. Its pathological examination revealed collision lesions of RNs at different histopathological stages and CAPNON lesions, and transitional lesions exhibiting combined RN and CAPNON features, with immune cell infiltrates. Our findings provide new evidence for an immune-mediated reactive process and insights into the pathogenies of CAPNON.

Bilateral epibulbar pseudorheumatoid nodulosis with a review of ocular adnexal palisading granulomas.

We describe the clinical, histopathologic, and immunohistochemical characteristics of episcleral/conjunctival pseudorheumatoid nodulosis, a new granulomatous entity that belongs among a group of related lesions. Specifically, pseudorheumatoid nodulosis should be differentiated from solitary rheumatoid nodules, rheumatoid nodulosis, accelerated rheumatoid nodules and nodulosis, and solitary pseudorheumatoid nodules. A 53-year-old man presented with bilateral painless, large, faintly yellow-gray, partially immobile, solid, circumscribed, and occasionally confluent episcleral nodules of several months' duration. He had never had clinical rheumatoid arthritis and was rheumatoid factor negative. Biopsy revealed multiple, merging episcleral/conjunctival, nonulcerated, palisading granulomas with variably sized central zones of necrobiosis of collagen. Abundant palisading CD68/163 + histiocytes admixed with fibroblasts surrounded the necrobiotic foci, which failed to stain with Alcian blue for mucopolysaccharides. No fibrinoid deposits were detected. Numerous CD3+ T lymphocytes, fewer CD 20 + B lymphocytes, and a smaller subpopulation of CD138 + plasma cells were present. Numerous CD1a + Langerhans cells were scattered among the palisading histiocytes and overlying epithelium. Immunohistochemical stains for immunoglobulins revealed concentrations of IgG, IgM, and IgA, but not IgE, in the necrobiotic zones. Special stains did not reveal evidence of infection nor did polarization microscopy display any foreign material. An extensive systemic and serologic workup was negative. We review simulating palisading or other nonrheumatic granulomas that should be distinguished from pseudorheumatoid nodules or nodulosis and explore therapeutic options.

Multiple myeloma masquerading as severe seropositive rheumatoid arthritis with subcutaneous nodules and mononeuritis multiplex.

Multiple myeloma can rarely mimic seronegative rheumatoid arthritis (RA). We report a 55-year-old woman who presented with longstanding deforming polyarthritis with extensive subcutaneous nodules, tenosynovitis, anti-cyclic citrullinated peptide positivity and mononeuritis multiplex. Even though the clinical picture was consistent with seropositive RA, the absence of bone erosion or joint space narrowing on hand and knee radiographs led us to question the diagnosis of RA. Further investigation revealed a diagnosis of multiple myeloma with cutaneous amyloid deposits, based on serum immunofixation, bone marrow aspiration and biopsy of a subcutaneous nodule. The only clue to suspect myeloma from the basic investigations and clinical examination was mild hypercalcemia. This case serves to reiterate the need to maintain a heightened suspicion for other diagnoses even when RA appears most likely.

Incidence and classification of cutaneous manifestations in rheumatoid arthritis.

BACKGROUND AND OBJECTIVE: There have only been few studies examining rheumatoid arthritis (RA)-related skin manifestations in larger patient populations. Herein, we present current data on the prevalence and spectrum of cutaneous lesions in RA, addressing disease activity scores, anti-CCP antibodies as well as novel pharmacological approaches. PATIENTS AND METHODS: Between November 2006 and July 2007, 214 patients with RA treated at the Division of Rheumatology, University Hospital Jena, Germany, were prospectively examined. RESULTS: 27.5 % of patients exhibited RA-related skin manifestations, almost all of which were rheumatoid nodules. These lesions occurred significantly more frequently in patients with longstanding disease, those testing positive for rheumatoid factor and anti-CCP-antibodies, as well as individuals on leflunomide and TNF-alpha antagonists. Comparatively lower prevalence rates were observed for palisading neutrophilic and granulomatous dermatitis and rheumatoid vasculitis. CONCLUSIONS: Despite increasingly early treatment of RA and use of novel pharmacological agents, there is a high prevalence of rheumatoid nodules, which represent the most common cutaneous manifestation in RA. The higher prevalence of rheumatoid nodules in patients on leflunomide and TNF-alpha antagonists might be an indication that pharmacological treatment has only limited effects on their formation, possibly due to pathogenetic pathways that are only inadequately affected by drug therapies. By contrast, palisading neutrophilic and granulomatous dermatitis and rheumatoid vasculitis appear to respond better to novel pharmacological agents.

Exaggerated circulating Th-1 cytokine response in early rheumatoid arthritis patients with nodules.

BACKGROUND: Immunohistochemical studies of the rheumatoid nodule (RN) suggest it is a Th1 granuloma, with focal vasculitis, yet the pathogenesis remains unclear and little is known about circulating cytokines in these patients. OBJECTIVE: We studied circulating cytokines in DMARD-naïve RA patients to investigate associations with subcutaneous RN. METHODS: 149 DMARD-naïve adults with early RA (symptom duration ≤ 2 years) were assessed using the Simplified Disease Activity Index (SDAI), and hand and feet radiographs were scored using the modified Larsen method. Circulating cytokines and growth factors representative of T-helper cell 1(Th1) and Th2 cell, macrophages, and fibroblasts were measured using the Bio-Plex® suspension array system. RESULTS: Of 149 patients, 34 (22.8%) had subcutaneous RN, and these patients had more severe disease with higher mean swollen joint counts (p=0.02), SDAI (p=0.04) and modified Larsen scores (p=0.004). There were no differences in Rheumatoid Factor or anti-cyclic citrullinated peptide antibody positivity between patients with RN and those without RN. Patients with RN showed significantly higher levels of circulating IL-12 (p=0.02), IL-2 (p=0.048), and VEGF (p=0.033) levels, with a trend towards higher levels of IL-7 (p=0.056), IFN-γ (p=0.059) and IL-8 (p=0.074) compared to those without RN. CONCLUSIONS: DMARD-naïve early RA patients with RN had more severe disease than those without RN, and showed an exaggerated circulating Th1 and macrophage cytokine profile.

Association of anticyclic citrullinated peptide antibodies with extra-articular manifestations, gender, and tabagism in rheumatoid arthritis patients from southern Brazil.

Gender and environmental factors are known to influence the clinical heterogeneity and outcome of rheumatoid arthritis (RA). Some variables have been suggested to be associated with the severity of the disease, which can be of great value in the correct management of RA patients. The purpose of this study was to investigate the associations among anticyclic citrullinated antibody (anti-CCP2) positivity, extra-articular manifestations (EAM), gender, and tobacco exposure in a Brazilian RA population. We performed a transversal study comprising 156 RA patients which were investigated for EAM, functional class, presence of anti-CCP2, and IgM rheumatoid factor (IgM-RF). The determination of anti-CCP2 was performed using enzyme immunoassay (ELISA) kits and IgM-RF by latex agglutination test. Clinical and demographical data were obtained through review of charts. Anti-CCP positivity intensity was directly correlated with tobacco smoking, sex, and the development of rheumatoid nodules. Intense anti-CCP2 reaction was 19.8-fold higher in females vs. males, 2.7-fold higher in tobacco vs. non-tobacco users, 7.7-fold higher in female vs. male tobacco users, and 5.15-fold higher in patients with rheumatoid nodules. Tobacco smoking, gender, and rheumatoid nodules are significantly correlated with anti-CCP2 positivity in Brazilian RA patients.

Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis.

OBJECTIVE: To examine the association of smoking with clinical and serological features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE). METHODS: In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current versus past versus never and pack-years of exposure) with anti-cyclic citrullinated peptide antibody, rheumatoid factor (RF) (IgM and IgA), rheumatoid nodules and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes. RESULTS: Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05 to 2.88) and nodules (OR = 2.43; 95% CI 1.13 to 5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-cyclic citrullinated peptide antibody, IgM-RF or radiographic erosions. There was also no evidence of a biological or statistical SE-smoking interaction for any of the outcomes examined. CONCLUSIONS: This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.

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.

Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis.

OBJECTIVE: In the K/BxN mouse model, autoantibodies against glucose-6-phosphate isomerase (GPI) cause arthritis. The relevance of this model for human disease remains a subject of controversy. We set out to determine whether GPI autoantibodies occur in patients with rheumatoid arthritis (RA) and, if so, at what stage of the RA. METHODS: Using an enzyme-linked immunosorbent assay, serum from 131 RA patients and 28 healthy controls was tested for autoantibodies against recombinant human GPI. Patients were grouped according to disease duration and presence of rheumatoid nodules, rheumatoid vasculitis, and Felty's syndrome, which are extraarticular complications of RA. RESULTS: Elevated levels of autoantibodies against GPI were present in 5% of patients with uncomplicated RA and 4% of controls. In RA complicated by extraarticular manifestations, anti-GPI antibodies were observed in 18% of patients with rheumatoid nodules, 45% of patients with rheumatoid vasculitis, and 92% of patients with Felty's syndrome. CONCLUSION: In patients with RA, autoantibodies to GPI are associated with the occurrence of extraarticular complications.

Cytokine profile of the rheumatoid nodule suggests that it is a Th1 granuloma.

OBJECTIVE: To define the cytokine profile within rheumatoid subcutaneous nodules, and to determine whether the destructive inflammatory process in this lesion displays features of a lymphocyte-driven Th1 or Th2 granuloma. METHODS: Subcutaneous nodules excised from 10 patients with rheumatoid arthritis were examined. Transcripts for interleukin 1beta (IL-1beta) IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-15, IL-18, and for tumor necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma) were detected by reverse transcription-polymerase chain reaction of extracted RNA. RESULTS: Nine of 10 nodules contained transcripts for IFNgamma. We observed no evidence for the expression of IL-2, IL-4, or IL-5 among the lymphokine genes analyzed. Transcripts for TNFalpha, IL-1beta, IL-10, IL-15, and IL-18 were present in all 10 nodules. Transcripts for IL-12 were present in all but one nodule. Expression of IL-13 messenger RNA was observed in only 5 nodules. CONCLUSION: The cytokine profile within the rheumatoid nodule (i.e., presence of IFNgamma but not IL-2, and prominent expression of IL-1beta and TNFalpha together with IL-12, IL-18, IL-15, and IL-10) is similar to the profile of cytokines in the synovial lesion of rheumatoid arthritis, which is generally accepted as being attributable to a Th1-mediated inflammatory mechanism. Our results suggest that damage to affected synovial membrane or subcutaneous tissue is caused by the same inflammatory mechanisms, and that the nodule is a Th1 granuloma.

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.

Cells expressing dendritic cell markers are present in the rheumatoid nodule.

OBJECTIVE: To determine if dendritic antigen-presenting cells (DC) are present in rheumatoid nodules, as has been reported in the synovial lesions of rheumatoid arthritis. METHODS: Nodules (n = 14) were examined with monoclonal antibodies (Mab) recognizing the DC differentiation/activation markers CD83, CMRF44, and CMRF56 and an antibody recognizing the CD1a antigen present on epithelial tissue associated DC. Results. Cells expressing CMRF44 were common in rheumatoid nodules, comprising 22% of nucleated cells versus 13% in synovial membranes (n = 10). Cells positive for CD1a (5%) and CD83 (2%) were less common. A majority (86%) of CMRF44 positive cells were also positive for the macrophage marker CD14. This left a significant minority of putative DC that were single stained with CMRF44. CONCLUSION: Cells bearing DC markers are as frequent in the rheumatoid nodule as in the synovial lesions. A majority are "indeterminate" cells that are CD14 positive but a proportion are single stained putative DC. The lack of lymphoid collections containing DC and T and B lymphocytes in the nodule suggests that local presentation of antigen may not occur in the rheumatoid nodule, as is thought to be the case in synovial membranes containing lymphoid follicles. This difference could potentially be explained by different states of activation, and differentiation of DC within the 2 lesions.

HLA DRB1* alleles in rheumatoid nodulosis: a comparative study with rheumatoid arthritis with and without nodules.

Rheumatoid nodulosis (RN) is a rare condition associating rheumatoid nodules, episodes of arthritis, cystic bone lesions and, generally, positive rheumatoid factors (RF). It is considered a benign variant of rheumatoid arthritis (RA). In this study, we determined the HLA DRB1* alleles of our RN patients and compared the distribution of these alleles to those of 74 healthy controls and 104 RA patients with and without nodules. Four RN patients were observed. All had subcutaneous nodules and RF were negative in three patients. Of the 104 RA patients, 18 had nodules (nodRA). Systemic manifestation (including vasculitis, peripheral neuropathy or lung involvement) were found in seven of these nodRA cases (33.8%) and most had positive RF and erosive changes on X-rays. Only one RN patient had a RA-associated allele (DRB1*0101). The frequencies of the HLA DRB1* alleles encompassing the "rheumatoid" shared epitope were similar to those of other RA series: *0101, 34.6% (P = 0.03 compared with controls); *0401, 26.9% (P < 0.0001); *0404, 12.5% (P = 0.04); *0405, 4.8% (P = 0.8); *1001, 8.6% (P = 0.5). Of the nodRA and seronegative RA patients, 77.7% and 53.3%, respectively, presented the shared epitope. Thus, there was a tendency to decreased expression of the RA-associated alleles in RN (25%) compared with nodRA and seronegative RA patients. This study is restricted by the small number of tested RN patients, but the results suggest that the RA-associated alleles are poorly expressed in RN.

Cigarette smoking and rheumatoid arthritis severity.

OBJECTIVES: Cigarette smoking may influence rheumatoid arthritis (RA) disease incidence and may have direct biological effects on the lungs and systemically. This study sought to determine if cigarette smoking is associated with RA disease severity. METHODS: Clinical evaluations of patients seen in the University of Iowa rheumatology and orthopaedic ambulatory clinics were conducted. A letter of interest was mailed to 1701 patients who were first assigned an ICD-9-CM diagnostic code for RA in one of these clinics. A total of 857 patients expressed interest and were offered a clinical examination and 395 were evaluated over an 18 month period. Of these, 336 satisfied examiner criteria for prevalent RA and were included in the analysis. The disease characteristics and arthritis care utilisation of these patients seemed representative of prevalent cases in the general community. RA disease severity was assessed by radiographic bone erosions (graded as either present/ absent and using the Larsen system), rheumatoid factor seropositivity, and presence of subcutaneous rheumatoid nodules. RESULTS: Pack years of cigarette smoking was significantly associated with rheumatoid factor seropositivity (p = 0.0001), radiographic erosions (p = 0.024), and nodules (p = 0.051). After adjustment for potential confounders, smokers with > or = 25 pack years were 3.1 times more likely to be rheumatoid factor positive (95% CI 1.7, 5.6) and 2.4 times more likely to show radiographic erosions (95% CI 1.2, 4.5) than never smokers. Less severe radiographic disease seemed to be more strongly associated with cigarette smoking than more severe disease. CONCLUSION: Cigarette smoking may adversely influence the severity of RA in a potentially dose dependent fashion.

Rheumatoid nodules of the larynx.

Two unique cases of rheumatoid nodules affecting the larynx are reported. These subcutaneous nodules represent localized laryngeal involvement from autoimmune disorders. The otolaryngologist should be aware of these possibilities as part of the differential diagnosis in the workup of dysphonia.

Immunopathology of subcutaneous rheumatoid nodules.

Nodules obtained from five patients with classical seropositive rheumatoid arthritis were studied by an immunofluorescence technique using polyclonal antibodies to IgG, IgA, IgM, C3c, and fibrin, and monoclonal antibodies to the terminal (C5b-9) complement complex (reaction with a neoantigen in C9 revealed during activation), DR antigens, T cells, macrophages, and interdigitating cells. In all instances the central necrotic areas stained strongly for fibrin and more weakly for IgG, IgA, IgM, C3, and terminal complement complex. The surrounding palisading cells reacted with antibodies to DR and macrophages. In the peripheral granulomatous tissue most of the lymphocytes reacted with the antibodies to T cells, whereas various amounts of the larger mononuclear cells were stained by antibodies to DR antigens, macrophages, and interdigitating cells. In all instances the walls of some of the smaller vessels in the granulomatous tissue stained for fibrin, C3, and terminal complement complex. Plasma cells were not seen except for scattered IgM cells in one nodule. These results support the view that the palisading cells are derived from macrophages, and indicate that there is vasculitis with activation of C3 and the terminal complement pathway in the granulomatous tissue.

Phenotypic markers of lymphocyte and mononuclear phagocyte activation within rheumatoid nodules.

We investigated rheumatoid subcutaneous nodules using monoclonal antibodies recognizing functional determinants on mononuclear phagocytes (Mph) and lymphocytes. Mph at the center of rheumatoid nodules showed strong expression of the leukocyte intergrins CR3 and p150,95 which would be consistent with the presence of a central chemotactic stimulus. Mph expression of FcR1, a gamma interferon regulated molecule, was decreased in 5/13 cases despite strong expression of MHC class II. There was a variable unstructured infiltrate of T lymphocytes, a majority of which were CD8 positive. Lymphocytes showed increased MHC class II expression but interleukin 2 receptor expression was low. We discerned no relationship between the number, distribution or phenotype of the T cell infiltrate and the phenotype of the predominant Mph population.

[Analysis of distribution of histocompatibility antigens class I and II in children with rheumatoid arthritis]. / Analiz raspredeleniia antigenov I i II klassov sistemy HLA u detei s revmatoidnym artritom.

The authors studied distribution of antigens HLA A, B, C in 115 children and of antigens HLA DR in 102 children of the Russian nationality with classic or diagnosed juvenile rheumatoid arthritis (JRA). A rise in the frequency of antigens B21, B27 and DR3 was noted as compared to the control values. Then distribution of HLA-antigens was analysed in separate groups of patients depending on the nature of the clinical course of JRA. It was characteristic of patients of patients depending on the nature of the clinical course of JRA. It was characteristic of patients with mono-oligoarthritis with an polyarticular form of JRA to exhibit a rise in the frequency of antigens B27 and DRW8, with uveitis--of antigens A2, B27 and DRW8, with a high degree of activity of the inflammatory process--B21, with an allergic variant--B21, with an articulovisceral form--B21, DR3 and DR4, with Still's disease--DR3, rheumatoid nodes--DR2 and DR3. Thus, specificity of associations was determined in most of the cases by the nature of JRA clinical course. The authors confirm the number of associations previously described in the literature abroad.