Rheumatoid arthritis is a systemic inflammatory autoimmune disease. It is characterized by a symmetric polyarthritis. The various manifestations are presented in the outline below.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis and Treatment Commonly Used Terms Internet Links
Epidemiology of rheumatoid arthritis: determinants of onset, persistence and outcome.
ARC Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester, M13 9PT, UK
Best Pract Res Clin Rheumatol 2002 Dec;16(5):707-22 Abstract quote
Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease. There is some evidence that it may have been brought from North America to Europe during the 18th century.
Its arrival in rural parts of the developing world is still more recent. The incidence and prevalence of RA appear to have fallen in Europe, North America and Japan in the last 50 years. During this time the peak age of onset has risen. Risk factors for the development of RA include genetic factors, an adverse pregnancy outcome, smoking, obesity and recent infections. The oral contraceptive pill and some dietary constituents may be protective.
Older age and female gender are risk factors both for the development of RA and for a worse outcome. This risk factor profile offers some opportunities for primary and secondary prevention. However, treatment is the greatest determinant of RA outcome.
Epidemiology and genetics of rheumatoid arthritis.
Silman AJ, Pearson JE.
ARC Epidemiology Unit, School of Epidemiology & Health Sciences, University of Manchester, Manchester, UK.
Arthritis Res 2002;4 Suppl 3:S265-72 Abstract quote
The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5-1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan.
These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases.
The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-gamma and other cytokines).
Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein-Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive.
There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.
DISEASE ASSOCIATIONS CHARACTERIZATION CUTIS LAXA
Acral localized acquired cutis laxa associated with rheumatoid arthritis
Franco Rongioletti, MD
Maurizio Cutolo, MD
Piera Bondavalli, MD
Alfredo Rebora, MD
J Am Acad Dermatol 2002;46:128-30 Abstract quote
We report the first case of the acral localization of the acquired form of cutis laxa associated with severe rheumatoid arthritis. The skin laxity was preceded by episodes of itching and swelling of the hands and feet. Histopathology showed that the elastic fibers were lost in the areas of cutis laxa and decreased in adjacent skin.
The pathogenetic relationship with rheumatoid arthritis or the intake of related drugs is discussed.
PYODERMA GANGRENOSUM Start as red papulopustules
Progress to ulcers
Undermined violaceous border
Complex associations between HLA-DRB1 genes and female rheumatoid arthritis: results from a prospective study.
Gonzalez-Escribano MF, Rodriguez R, Valenzuela A, Garcia A, Nunez-Roldan A.
Servicio de Immunologia and Servicio de Reumatologia, Hospital Universitario Virgen del Rocio, Servicio Andaluz de Salud, Seville, Spain.
Hum Immunol 1999 Dec;60(12):1259-65 Abstract quote
We followed 138 Spanish patients (37 men and 101 women) with rheumatoid arthritis (RA) to analyze whether patient sex influenced the HLA-DRB1 associations with disease susceptibility.
Results showed that, although a high increase of the shared epitope (SE) was observed in both genders, distribution of HLA-DRB1 specificities differs from males to females: DR1 was increased among male patients, whereas DR4 as well as DR10 were preferentially associated with female RA. To further explore whether this phenomenon operates either on susceptibility or on disease progression, 82 patients (25 males and 57 females) among the whole group were followed during the first 8 to 10 years of their disease. Results from this prospective study showed that the association of the SE with radiological disease severity was found in both male and female patients, although it was stronger among the latter group. Interestingly, DR1- as well as DR4-related alleles contributed to the high frequency of SE among female patients with early small-joints severe RA and/or long-term large-joint erosions.
These results suggest that HLA polymorphism might be involved in RA pathogenesis through two mechanisms: (a) in combination with patient sex, operating in disease induction; and (b) independent of patient sex, influencing disease severity and progression.
Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF).
Barrera P, Balsa A, Alves H, Westhovens R, Maenaut K, Cornelis F, Fritz P, Bardin T, Ceu Maia M, Lopes-Vaz A, Pascual Salcedo D, de la Concha E, Radstake T, van de Putte LB, Migliorini P, Prudhomme JF, Charron D, Spyropoulou M, Mendes A, Spaepen M, Martinez M, Stavropoulos C;
European Consortium on Rheumatoid Arthritis Families. Department of Rheumatology, University Hospital, Nijmegen, The Netherlands.
J Rheumatol 2001 May;28(5):968-74 Abstract quote
OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger influence than in patients with sporadic RA. We investigated the NIMA hypothesis in a large cohort of European patients with familial RA.
METHODS: The distribution of NIMA, noninherited paternal antigens (NIPA), and inherited HLA-DR antigens was assessed in patients with familial RA from all family sets collected from 1996 onwards by the ECRAF. HLA-DRB1 oligotyping from patients and all available nonaffected siblings and parents was carried out. Familial RA was defined by the presence of at least 2 affected first-degree relatives in the same family. The frequencies of HLA-DR NIMA and NIPA were compared using odds ratios after stratification for HLA-DR*04, *0401, and/or *0404 and shared epitope (SE) status. NIMA/NIPA that coincided with inherited parental HLA-DR antigens were considered redundant and were excluded from analysis.
RESULTS: NIMA and NIPA could be analyzed in 165 RA patients with familial RA and 84 nonaffected siblings. Patients were predominantly female, rheumatoid factor positive, and had erosive disease (81, 75, and 84%, respectively). Possession of HLA-DR*04 and *0401/*0404 alleles tended be more frequent in patients than in nonaffected siblings but this did not reach statistical significance. SE possession was similar in patients and healthy siblings, although the former had a double dose SE more often (37.6 vs 17.8%; p = 0.002). Transmission of SE encoding alleles from parents to offspring was skewed only in patients [OR (95% CI) 3.56 (2.55-4.95) vs 1.16 (0.75-1.79) in nonaffected siblings]. Using the NIPA as control, the frequencies of HLA-DRB1*04, *0401/*0404, and SE positive NIMA were not increased in patients lacking these susceptibility alleles. The frequencies of NIMA encoding susceptibility alleles in DR*04 and *0401/*0404 negative patients were lower than in nonaffected siblings.
CONCLUSION: Our results corroborate the association between RA and inherited SE alleles and do not support a role for noninherited HLA-DR maternal antigens in the susceptibility for familial RA.
Time lag between active joint inflammation and radiological progression in patients with early rheumatoid arthritis.
Matsuda Y, Yamanaka H, Higami K, Kashiwazaki S.
Institute of Rheumatology, Tokyo Women's Medical College, Japan.
J Rheumatol 1998 Mar;25(3):427-32 Abstract quote
OBJECTIVE: To determine clinical variables useful in predicting the prognosis of patients with early rheumatoid arthritis (RA) by investigating the relationship between clinical variables and radiological progression.
METHODS: One hundred eighteen patients with early RA whose symptoms developed within the previous year were enrolled in a prospective study. Data from the 98 patients who completed the 2 year study were analyzed, using the number of erosive joints and Larsen's score as the outcome of RA.
RESULTS: Increases in the number of erosive joints at 12 months after entry into the study were significantly correlated with the number of swollen joints (r = 0.510), erythrocyte sedimentation rate (ESR) (r = 0.404), and C-reactive protein (CRP) (r = 0.487) at 6 months. The same results were seen using Larsen's score as the measure of outcome. The average number of erosive joints or mean Larsen's score at 12 months was higher in patients whose levels of CRP were high at 6 months and suppressed by 12 months, but increased much less in patients whose levels of CRP were successfully suppressed by 6 months. More joint erosions were noted in patients with positive rheumatoid factor (RF) than in RF negative patients.
CONCLUSION: Joint erosions appeared with a certain time lag after active synovitis. Earlier introduction of effective treatment is recommended for the prevention of RA joint damage. The presence of RF, number of swollen joints, ESR, and levels of CRP at 6 months after starting therapy are the most useful variables to predict radiological progression in patients with early RA.
LABORATORY PERIPHERAL BLOOD Thrombocytosis
Serum amyloid A in the assessment of early inflammatory arthritis.
Cunnane G, Grehan S, Geoghegan S, McCormack C, Shields D, Whitehead AS, Bresnihan B, Fitzgerald O.
Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland.
J Rheumatol 2000 Jan;27(1):58-63 Abstract quote
OBJECTIVE: Acute phase serum amyloid A (A-SAA) has been reported to be more sensitive than C-reactive protein (CRP) as a marker of disease activity. It may function in immune regulation and is linked to the development of secondary amyloidosis. We investigated the profile of A-SAA in early inflammatory arthritis and compared A-SAA with CRP and erythrocyte sedimentation rate (ESR) in relation to diagnosis and disease activity.
METHODS: Using a sensitive and specific ELISA, A-SAA was measured in the serum of 140 patients with early arthritis (disease duration 2 weeks to 24 mo, mean 6 mo). CRP was determined using a standard ELISA; ESR and clinical disease activity variables were also recorded.
RESULTS: Sixty-four patients had rheumatoid arthritis (RA), 19 psoriatic arthritis (PsA), 28 undifferentiated arthritis (UA), and 29 other forms of arthritis. A-SAA levels correlated with both CRP (r = 0.73, p = 0.0001) and ESR (r = 0.6, p = 0.0001). The magnitude of the A-SAA response was greater than either the CRP or ESR, and very high A-SAA levels were observed in disease as early as 2 weeks. Highest A-SAA concentrations occurred in RA (median 70.3 mg/l, maximum 1542) compared with the other groups (medians, PsA: 33 mg/l; UA: 12.3 mg/l; other arthritis: 11.2 mg/l), with values > 520 mg/l observed exclusively in RA. A-SAA, unlike CRP or ESR, could distinguish patients with a final diagnosis of RA from those who had persistent UA. In RA, A-SAA provided the strongest correlations with clinical measurements of disease activity. Clinical improvement was also best represented by A-SAA, while disease deterioration was associated with a significant increase in A-SAA values, but not CRP or ESR.
CONCLUSION: Compared with ESR or CRP, A-SAA correlates best with markers of disease activity, and in patients with recent onset arthritis, very high levels of SAA occur exclusively in RA. As A-SAA is sensitive to change and accurately reflects alterations in disease status, it is the best marker available for the assessment of inflammatory joint disease.
Antineutrophil cytoplasmic antibodies in patients with early rheumatoid arthritis: an early marker of progressive erosive disease.
Mustila A, Paimela L, Leirisalo-Repo M, Huhtala H, Miettinen A.
Tampere University Hospital, Finland.
Arthritis Rheum 2000 Jun;43(6):1371-7 Abstract quote
OBJECTIVE: To evaluate the clinical associations of antineutrophil cytoplasmic antibodies (ANCA) in patients with early rheumatoid arthritis (RA), as well as the possible predictive role of ANCA. We also assessed the overlap of ANCA with other specific serologic markers of RA.
METHODS: Eighty-two RA patients with symptoms for < or = 12 months were studied for the presence of ANCA by immunofluorescence and specific enzyme immunoassays. ANCA were determined and clinical, radiographic, and laboratory data were collected at study entry and later at 12, 36, 60, and 84 months.
RESULTS: In 2 patients, the first serum samples (obtained at study entry) were no longer available for the determination of ANCA. Perinuclear ANCA (pANCA) were found in 40 patients (50%), and atypical cytoplasmic ANCA were found in 3 patients (4%) at study entry. Perinuclear ANCA-positive patients were significantly more frequently positive for rheumatoid factor (78%) than were ANCA-negative patients (54%) (P = 0.0297). Fifty-five percent of pANCA-positive patients and 22% of ANCA-negative patients were positive for antiperinuclear factor (P = 0.0044). Similarly, pANCA-positive patients had antikeratin antibodies more frequently than did ANCA-negative patients (35% versus 20%). During a 7-year followup, the progress of radiographic joint destruction, assessed with Larsen scores, was significantly more rapid in patients who were pANCA positive at study entry than in those who were ANCA negative (P = 0.0015). Also, the mean titer of pANCA at study entry was significantly higher in those patients who subsequently had advanced radiographic joint destruction at 60 and 84 months. The association of pANCA with rapid radiographic destruction in patients with early RA was further corroborated by a logistic regression analysis that selected pANCA positivity as an independent and statistically significant predictor of rapid radiographic joint destruction.
CONCLUSION: In patients with early RA, pANCA are associated with specific serologic markers of RA and predict rapid radiographic joint destruction.
ANTI-CCP C REACTIVE PROTEIN
Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis.
Arthritis Research Center, Wichita, KS 67214, USA.
J Rheumatol 1997 Aug;24(8):1477-85 Abstract quote
OBJECTIVE: To determine the comparative usefulness of the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the assessment of rheumatoid arthritis (RA) activity and to provide tables and nomograms of normative data in RA allowing the linking and interchange of test values.
METHODS: We studied 774 patients with RA seen in the clinic by obtaining complete rheumatologic examinations and laboratory studies. Clinical variables included visual analog scale pain and global severity, joint count, functional disability, depression, and a composite measure of disease activity. In addition, we measured ESR and hemoglobin, and rheumatoid factor (RF), CRP, IgG, IgA, IgM, haptoglobin, alpha 1-antitrypsin, albumin, pre-albumin, and C4 by nephelometry.
RESULTS: Median values for CRP were 0.82 mg/dl and ESR 26 mm/h. The average correlation with 7 clinical variables was 0.248 for ESR compared to 0.259 for CRP. But partial correlation analysis showed that a substantial portion of the correlation with ESR is explained by the effect of immunoglobulins, RF, and hemoglobin rather than the acute phase response. Twenty-eight percent of results were discordant between ESR and CRP, and this discordance was explained by the above factors. When discordance occurred, CRP was a better measure of disease activity than ESR.
CONCLUSION: Simple comparisons between ESR and CRP suggest that both tests are similar, but partial correlation analysis indicates that part of the correlation between ESR and clinical variables comes from non-acute phase factors. These factors, in turn, are responsible for most of the discordance between ESR and CRP results. Thus, CRP appears to be the better test regarding measurement of the acute phase. Because ESR is sensitive to immunoglobulins and RF, it may measure general severity better than CRP, even though it is a poorer measure of inflammation. This perhaps accounts for the relative equivalence of the tests. The combination of ESR and CRP yields useful information that is often not apparent when only a single test is used.
Equivalence of the acute phase reactants C-reactive protein, plasma viscosity, and Westergren erythrocyte sedimentation rate when used to calculate American College of Rheumatology 20% improvement criteria or the Disease Activity Score in patients with early rheumatoid arthritis.
Western Consortium of Practicing Rheumatologists. Paulus HE, Ramos B, Wong WK, Ahmed A, Bulpitt K, Park G, Sterz M, Clements P.
Department of Medicine, University of California Los Angeles, USA.
J Rheumatol 1999 Nov;26(11):2324-31 Abstract quote
OBJECTIVE: In an additive cohort of patients with early rheumatoid arthritis (RA), to determine the effect of substituting one acute phase reactant for another on the number of patients satisfying the American College of Rheumatology (ACR) 20% preliminary criteria for improvement, and on calculated Disease Activity Scores (DAS).
METHODS: A total of 251 patients with 6.4 months average disease duration had detailed clinical assessments at entry and 6, 12, and 24 months in a multicenter prospective longterm observational study. Matched erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and plasma viscosity (PV) assays were done at 366 time points. Disease modifying antirheumatic drugs were not started until after the baseline evaluation.
RESULTS: After 6, 12, and 24 months, 50%, 53%, and 57% of patients were responders, as defined by the ACR 20% improvement criteria. The difference in response rates when ESR, CRP, or PV was used as the acute phase reactant ranged from 0.4% at 12 months to 3% at 24 months. Percentile distributions of the 366 matched CRP, ESR, and PV values were used to prepare a nomogram that can be used to calculate the other acute phase reactant values if the value of one is known. When the nomogram was used to impute ESR values from observed PV or CRP values, average DAS scores calculated with the actual ESR values were not different from average DAS scores calculated from the imputed ESR values.
CONCLUSION: ESR, CRP, and PV are equally useful in calculating ACR 20% response rates in patients with active early RA. A nomogram can be used to impute ESR values from CRP or PV values; use of the imputed ESR values is as accurate as use of the actual ESR values to calculate average DAS.
Serum transferrin receptor levels in patients with rheumatoid arthritis are correlated with indicators for anaemia.
Chijiwa T, Nishiya K, Hashimoto K.
Second Department of Internal Medicine, Kochi Medical School, Nankoku City, Japan.
Clin Rheumatol 2001;20(5):307-13 Abstract quote
To measure serum soluble transferrin receptor (s-TfR) levels in patients with rheumatoid arthritis (RA), sera were obtained from 50 Japanese RA patients and 20 healthy subjects.
Both s-TfR and serum erythropoietin (EPO) levels were measured by enzyme-linked immunosorbent assay (ELISA). Routine laboratory tests were also performed, including peripheral blood analysis and determination of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), serum iron levels, total iron-binding capacity (TIBC) and serum ferritin levels.
The s-TfR levels in the 50 RA patients (mean +/- SD, 1,801 +/- 512 ng/ml) were significantly higher than those in the 20 control subjects (1,316 +/- 345 ng/ml). There were no differences in the values of s-TfR between men and women in either group, or between RA patients over and under 50 years old. Serum EPO levels in 47 RA patients were as low as 14.0 +/- 10.1 mlU/ml (mean +/- SD), ranging from 3.9 to 58.7 mIU/ml (normal range 2.8-17.2 mlU/ml), unrelated to low haemoglobin concentration. The s-TfR levels in RA patients showed negative correlations with red blood cell count, serum iron level and haemoglobin concentration, and positive correlations with ESR and serum EPO levels. However, there were no correlations between s-TfR level and markers of inflammation such as CRP, platelet count or RF titre.
In conclusion, s-TfR level in RA patients could be a marker of erythropoiesis rather than of joint inflammation.
Clinical and immunogenetic characteristics of European multicase rheumatoid arthritis families.
Balsa A, Barrera P, Westhovens R, Alves H, Maenaut K, Pascual-Salcedo D, Cornelis F, Bardin T, Riente L, Radstake TR, de Almeida G, Lepage V, Stravopoulos C, Spaepen M, Lopes-Vaz A, Charron D, Martinez M, Prudhomme JF, Migliorini P, Fritz P;
European Consortium on Rheumatoid Arthritis Families (ECRAF). Rheumatology Unit, University Hospital La Paz, 28046 Madrid, Spain.
Ann Rheum Dis 2001 Jun;60(6):573-6 Abstract quote
OBJECTIVE: To describe the characteristics of a new set of European families with affected sib pairs (ASP) collected by the European Consortium on Rheumatoid Arthritis Families (ECRAF) to replicate the results of our first genome scan. Potential gradients for disease severity in Europe and concordance within families were studied.
PATIENTS AND METHODS: From 1996 to 1998 European white families with at least two affected siblings were enrolled in the study. Demographic (sex, age at onset), clinical data (rheumatoid factor (RF), disease duration, erosive disease, extra-articular features (EF)), and HLA-DRB1 oligotyping were analysed.
RESULTS: 565 patients with rheumatoid arthritis (RA), belonging to 271 families including 319 affected sib pairs (ASP) were collected. Belgium, France, Italy, the Netherlands, Portugal, and Spain contributed 20, 96, 52, 24, 9, and 70 families, respectively. Sex (78% women), age at onset (mean 44 years), and RF positivity (79%) were similar among the countries. Differences were found in disease duration (11-18 years) and in the prevalence of erosive disease (70-93%), nodules (15-44%), subjective Sjogren's syndrome (5-38%), and EF (3-16%) (p<0.05 in all cases). A total of 22% RA sibs were shared epitope (SE) negative, whereas 47% and 30% carried one and two SE alleles respectively. Carriage of SE differed widely among countries (p<0.0001): no SE alleles (6-36%), one allele (43-60%), and two alleles (20-39%). SE encoding alleles were mainly DRB1*04 in the Netherlands and Belgium, whereas SE carriage was less common and evenly distributed between DRB1*01, *04, and *10 in Mediterranean countries. No concordance within families was found either in age/calendar year of onset (intraclass correlation coefficient <0.50) or in clinical and radiological features (kappa<0.22).
CONCLUSIONS: The differences in RA characteristics between European countries and within families underline the heterogeneity of the disease. No clear cut gradient of disease severity was seen in Europe.
JOINTS PIP and MCP joints of the hands LUNG Pleural effusions
HEART Pericarditis LYMPHATIC Lymphadenopathy SKIN
J Am Acad Dermatol. 2005 Aug;53(2):191-209; quiz 210-2. Abstract quote
Rheumatoid arthritis is a chronic inflammatory arthritis with significant extra-articular manifestations. Of note are unique cutaneous manifestations that the dermatologist may encounter.
This article will make the dermatologist more cognizant of these skin findings in patients with this systemic inflammatory disorder. It examines rheumatoid arthritis, focusing on the general nonspecific and disease-specific rheumatoid arthritic skin changes. Classic rheumatoid nodules, accelerated rheumatoid nodulosis, rheumatoid nodulosis, rheumatoid vasculitis, Felty syndrome, pyoderma gangrenosum, interstitial granulomatosus dermatitis with arthritis, palisaded neutrophilic and granulomatosis dermatitis, rheumatoid neutrophilic dermatitis, juvenile rheumatoid arthritis, and adult-onset Still disease are reviewed. Understanding the cutaneous expressions of rheumatoid arthritis may lead to early diagnosis, prompt treatment, and lower morbidity and mortality for the affected persons.
Learning objective At the completion of this learning activity, participants should be able to describe rheumatoid arthritis in terms of its epidemiology, etiology, pathogenesis, and general and specific cutaneous manifestations.
HISTOPATHOLOGICAL VARIANTS CHARACTERIZATION VARIANTS SKIN
Intravascular or intralymphatic histiocytosis associated with rheumatoid arthritis: A report of 4 cases.
Takiwaki H, Adachi A, Kohno H, Ogawa Y
J Am Acad Dermatol. 2004 Apr;50(4):585-90. Abstract quote
BACKGROUND: Various skin lesions occur in association with rheumatoid arthritis (RA).
OBSERVATION: We report a distinctive skin lesion observed in 4 patients with RA. All patients had RA for many years and developed asymptomatic, irregularly shaped erythema over the swollen elbow joints and the nearby part of the forearm. Histopathologically, all cases showed massive aggregates mainly composed of histiocytes in markedly dilated vessels in the dermis, accompanied by a dermal infiltrate of lymphocytes, plasma cells, neutrophils, or a combination of these. A total of 9 cases, including ours, showing similar histopathologic findings have been reported in the literature, of which 7 were associated with RA and presented relatively common clinical appearance.
CONCLUSION: In spite of some disagreement as to whether the dilated vessels are blood vessels or lymphatics, it is most likely that these 7 cases belong to the same clinical entity closely associated with RA.
The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients.
Magro CM, Crowson AN.
Department of Pathology, Ohio State University, Columbus, OH, USA; Central Medical Laboratories, Winnipeg, Manitoba, Canada; Departments of Dermatology and Pathology, University of Oklahoma; and Regional Medical Laboratory, St. John Medical Center, S. Utica, Tulsa, OK, USA.
J Cutan Pathol 2003 Jan;30(1):1-10 Abstract quote
INTRODUCTION: Rheumatoid arthritis (RA) is an idiopathic arthropathy syndrome that has a propensity to affect the small joints of the hands and feet with extra-articular manifestations comprising skin lesions, neuropathy, pericarditis, pleuritis, interstitial pulmonary fibrosis and a systemic polyarteritis nodosa (PAN)-like vasculitic syndrome. The most widely recognized skin lesion is the rheumatoid nodule. Other skin manifestations are poorly defined.
MATERIALS AND METHODS: Using a natural language search of the authors' outpatient dermatopathology databases, skin biopsies from 43 patients with RA were selected for retrospective analysis in an attempt to define the dermatopathological spectrum of RA and its clinical correlates.
RESULTS: The biopsies were categorized by the dominant histologic pattern, recognizing that in most cases there were additional minor reaction patterns. Palisading and/or diffuse interstitial granulomatous inflammation was the dominant pattern seen in 21 patients; the lesions included nodules, plaques and papules with a predilection to involve skin over joints. Besides interstitial histiocytic infiltrates and variable collagen necrobiosis, these cases also showed interstitial neutrophilia, vasculitis and pauci-inflammatory vascular thrombosis. The dominant morphology in 11 other patients was vasculopathic in nature: pauci-inflammatory vascular thrombosis, glomeruloid neovascularization, a neutrophilic vasculitis of pustular, folliculocentric, leukocytoclastic or benign cutaneous PAN types, granulomatous vasculitis, and lymphocytic vasculitis and finally occlusive intravascular histiocytic foci for which the designation of 'RA-associated intravascular histiocytopathy' is proposed. Rheumatoid factor (RF) positivity and active arthritis were common in this group, with anti-Ro and anticardiolipin antibodies being co-factors contributing to vascular injury in some cases. Immunofluorescent testing in three patients revealed dominant vascular IgA deposition. In nine patients, the main pattern was one of neutrophilic dermal and/or subcuticular infiltrates manifested clinically as urticarial plaques, pyoderma gangrenosum and panniculitis.
CONCLUSIONS: The cutaneous manifestations of RA are varied and encompass a number of entities, some of which define the dominant clinical features, such as the rheumatoid papule or subcutaneous cords, while others allude to the histopathology, i.e. rheumatoid neutrophilic dermatosis. We propose a more simplified classification scheme using the adjectival modifiers of 'rheumatoid-associated' and then further categorizing the lesion according to the dominant reaction pattern. Three principal reaction patterns are recognized, namely extravascular palisading granulomatous inflammation, interstitial and/or subcuticular neutrophilia and active vasculopathy encompassing lymphocyte-dominant, neutrophil-rich and granulomatous vasculitis. In most cases, an overlap of the three reaction patterns is seen. Co-factors for the vascular injury that we believe are integral to the skin lesions of RA include RF, anti-endothelial antibodies of IgA class, anti-Ro and anticardiolipin antibodies.
Rheumatoid nodules Deep dermal subQ nodules
Flesh colored to erythematous
Extensor arms, elbows, knees, feet, ears
High titer of RF
Aggressive erosive arthritis
J Cutan Pathol 1992;19:48-53
Digital pulp papules (Bywater's lesions)
Indurated subQ plaques
Rheumatoid neutrophilic dermatosis Urticarial plaques
Extensors arms and hands
Rheumatoid neutrophilic dermatitis in a woman with seronegative rheumatoid arthritis
Timothy S. Brown, MD
Paul K. Fearneyhough, MD
Jyoti B. Burruss, MD
Jeffrey P. Callen, MD
J Am Acad Dermatol 2001;45:596-600 Abstract quote
Rheumatoid neutrophilic dermatitis (RND) is an unusual cutaneous reaction in patients with rheumatoid arthritis (RA). RND is characterized by symmetric, erythematous papules, plaques, nodules, and urticarial lesions often located over the joints, extensor surfaces of the extremities, or the trunk.
This entity demonstrates an intense neutrophilic dermal infiltrate without vasculitis. All patients previously reported with RND had severe RA with relatively high titers of rheumatoid factor when tested. A 67-year-old woman had a 2-month history of multiple, tender, 4 to 8 mm erythematous, crusted papules and nodules that occurred in clusters on her anterior thighs, knees, and legs. She suffered from severe disabling seronegative RA.
RND may complicate seronegative RA.
INTERSTITIAL GRANULOMATOUS DERMATITIS Linear subQ cords
RHEUMATOID PAPULES Red to flesh-colored papules
PALISADED NEUTROPHIULIC GRANULOMATOUS DERMATITIS Tender red papules
Umbilicated, crusted, or ulcerated
Palisaded neutrophilic granulomatous dermatitis in rheumatoid arthritis.
Sangueza OP, Caudell MD, Mengesha YM, Davis LS, Barnes CJ, Griffin JE, Fleischer AB, Jorizzo JL.
Department of Dermatology, Wake Forest University, School of Medicine, Winston-Salem, North Carolina 27157-1072, USA.
J Am Acad Dermatol 2002 Aug;47(2):251-7 Abstract quote
Palisaded neutrophilic granulomatous dermatitis (PNGD) is an entity that has not been clearly defined either clinically or histopathologically. It is seen in patients with rheumatoid arthritis and other connective tissue diseases. In the past, many cases of PNGD have been described under several different names including palisaded neutrophilic and granulomatous dermatitis, linear subcutaneous bands, interstitial granulomatous dermatitis with cutaneous cords and arthritis, rheumatoid papules, and Churg-Strauss granuloma.
We report 7 additional cases of PNGD. Clinically, 6 patients presented with erythematous to violaceous plaques, papules, and nodules on multiple body sites; one presented with subcutaneous linear bands on the shoulder. Five had rheumatoid arthritis; one had adult-onset Still's disease; and one showed clinical signs of rheumatoid arthritis, although serologically the rheumatoid factor was negative.
On histologic examination, a spectrum of changes was observed ranging from urticaria-like infiltrates to leukocytoclastic vasculitis and granuloma annulare with neutrophils. We report these cases to expand the histologic spectrum of this entity and to further delineate the different forms of clinical presentation.
Expression of the histiocytic marker PG-M1 in granuloma annulare and rheumatoid nodules of the skin.
Groisman GM, Schafer I, Amar M, Sabo E.
Hillel Yaffe Medical Center, Hadera, HaEmek Medical Center, Afula, Carmel Medical Center, Haifa, Israel.
J Cutan Pathol 2002 Nov;29(10):590-5 Abstract quote
BACKGROUND: The expression of PG-M1, the most specific histiocytic marker, has not yet been studied in granuloma annulare (GA) and other palisaded granulomas of the skin. We evaluated the reactivity of PG-M1 with a series of GA and rheumatoid nodules (RN) to establish the sensitivity and potential usefulness of this marker in the diagnosis and characterization of these entities.
METHODS: Histological sections from 30 GA and 15 RN were immunostained with PG-M1. For comparison, additional sections were stained with KP-1 and lysozyme. The stains were recorded as negative, weakly positive (1+) and strongly positive (2+).
RESULTS: PG-M1 stained all cases of GA (100%). KP-1 and lysozyme stained 26 (86%) and 18 (60%) GA cases, respectively. PG-M1 exhibited a significantly stronger staining intensity (1.8 +/- 0.07) when compared with KP-1 (1.4 +/- 0.13) (p = 0.018) and with lysozyme (0.9 +/- 0.15) (p < 0.0001). All RN were stained by PG-M1 (100%). KP-1 and lysozyme stained 14 (93%) and six (40%) RN cases, respectively. PG-M1 staining intensity (1.6 +/- 0.13) was slightly higher than that of KP-1 (1.4 +/- 0.18) (p = 0.27) and significantly higher than that of lysozyme (0.4 +/- 0.13) (p < 0.0001).
CONCLUSIONS: PG-M1 is consistently and strongly expressed by the histiocytic population of GA and RN, being more sensitive and reliable than other histiocytic markers. We recommend its use in difficult cases in which the histiocytic nature of the lesion needs to be confirmed.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES AUTOIMMUNE DISEASES
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
The relation of radiographic changes to serum acute-phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis.
Spenshult's Rheumatism Hospital, Oskarstrom, Sweden.
Scand J Rheumatol 1988;17(2):123-9 Abstract quote
Radiographic parameters in 200 patients with rheumatoid arthritis (RA) were correlated with laboratory parameters, including hemoglobin (Hb), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), orosomucoid (OROS), immunoglobulin G (IgG), IgM, IgA, and rheumatoid factor (RF). CRP, OROS, and Hb showed a significant association with the severity and progress of radiographic parameters.
ESR and WARO showed a significant association with the severity of radiographic parameters in late RA only.
IgG, IgM, and IgA did not show any significant correlation with radiographic parameters.
HLA-DRB1 genes and disease severity in rheumatoid arthritis.
The MIRA Trial Group. Minocycline in Rheumatoid Arthritis.
Reveille JD, Alarcon GS, Fowler SE, Pillemer SR, Neuner R, Clegg DO, Mikhail IS, Trentham DE, Leisen JC, Bluhm G, Cooper SM, Duncan H, Tuttleman M, Heyse SP, Sharp JT, Tilley B.
University of Texas Health Science Center, Houston, USA.
Arthritis Rheum 1996 Nov;39(11):1802-7 Abstract quote
OBJECTIVE: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial.
METHODS: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression.
RESULTS: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope.
CONCLUSION: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.
HLA-DRB1 genes, rheumatoid factor, and elevated C-reactive protein: independent risk factors of radiographic progression in early rheumatoid arthritis.
Berlin Collaborating Rheumatological Study Group. Listing J, Rau R, Muller B, Alten R, Gromnica-Ihle E, Hagemann D, Zink A.
German Rheumatism Research Center, Berlin, Germany.
J Rheumatol 2000 Sep;27(9):2100-9 Abstract quote
OBJECTIVE: To evaluate the prognostic value of HLA-DRB1 antigens, rheumatoid factor (RF), and C-reactive protein (CRP) with the radiographic outcome of rheumatoid arthritis (RA).
METHODS: In total, 139 patients with early RA (< 2 years) were followed up. At the end of 3 year treatment with disease modifying antirheumatic drugs (DMARD) HLA genotyping and external radiographic scoring were performed. The time up to the first development of erosive disease [Ratingen radiographic score (RS) > 0, > 5, > 10] was compared by methods of survival analysis.
RESULTS: At 4 years' disease duration, DRB1*04 or DRB1*01 positive patients had RS > 0 or > 10 (73% and 27%, respectively) significantly more frequently than DRB1*04 or DRB1*01 negative patients (37% and 7%, respectively). Nearly independently of the genetic predisposition, RF and elevated CRP at the start of DMARD treatment were predictive for erosive RA at 4 years. Elevated CRP (> or = 15 mg/l) increased the probability of erosive RA in DRB1*04 or DRB1*01 positive patients from 64.0% (in patients with CRP < 15 mg/l) to 83.9%, and in DRB1*04 and DRB1*01 negative patients from 18.8% to 70.1%. The corresponding figures for RF+ and RF- patients were 58.2% and 82.5% in HLA predisposed patients and 23.5% and 60.2% in those who were negative for DRB1*04 and DRB1*01. The probability of a RS > 10 was 40.9% for HLA predisposed patients with elevated CRP. In contrast, no case with RS > 10 was found in 43 patients who had neither of these 2 risk factors.
CONCLUSION: Our findings support that HLA predisposition plays an important role with regard to radiographic progression. However, this effect is modified by RF serum concentration and disease activity.
Relative contributions of the components of the American College of Rheumatology 20% criteria for improvement to responder status in patients with early seropositive rheumatoid arthritis.
Paulus HE, Bulpitt KJ, Ramos B, Park G, Wong WK;
Western Consortium of Practicing Rheumatologists. University of California, Los Angeles, Schools of Medicine and Public Health, USA.
Arthritis Rheum 2000 Dec;43(12):2743-50 Abstract quote
OBJECTIVE: To evaluate factors that influence the responses defined by the American College of Rheumatology (ACR) 20% criteria for improvement in rheumatoid arthritis (RA).
METHODS: ACR 20% and 50% response rates were calculated from data collected for the intervals 0-6, 0-12, and 0-24 months for 180 RA patients participating in the Western Consortium of Practicing Rheumatologists long-term observational study of early seropositive RA (mean +/- SD duration of RA at study entry 6.0 +/- 3.4 months). Analyzable cases were patients with paired data for tender and swollen joint counts plus at least 3 of the following criteria: physician's and patient's global assessments of disease activity and patient's score for pain (by visual analog scale), physical function score on the Health Assessment Questionnaire (HAQ), and levels of an acute-phase reactant. Response rates were then recalculated by 3 different methods: 1) using only cases with complete paired data for all criteria, 2) sequentially assuming no improvement in each of the 5 secondary criteria, and 3) substituting grip strength for HAQ scores.
RESULTS: Using 464 paired observations for all analyzable cases, ACR 20% (50%) improvement rates were 52.6% (33.0%), compared with 55.6% (34.8%) for 365 paired observations from the cases with complete data. Decreases in ACR response rates when secondary criteria were sequentially set at "no improvement" ranged from 11.7% (pain at 0-6 months) to 1.2% (C-reactive protein at 0-12 months), but these were not statistically different by the kappa statistic. Overall numerical rankings of the relative contributions of the secondary criteria to the ACR 20% or 50% response rates were physician's global assessment, pain, HAQ, patient's global assessment, and acute-phase reactant. Only 7.8% of paired grip strength observations showed > or =20% improvement, compared with 71% of paired HAQ observations.
CONCLUSION: The use of all "analyzable" cases (paired data for tender and swollen joint counts plus > or =3 of the 5 secondary criteria) increases the number of subjects and only slightly decreases the ACR response rate compared with analyses limited to cases with complete data. The contributions of the secondary criteria are not statistically different, supporting their equal weighting in the ACR definition of improvement. The ACR 20% response rates are higher when the HAQ, rather than grip strength, is used to measure physical function.
MALIGNANCIES No Evidence for Increased Risk of Cutaneous Squamous Cell Carcinoma in Patients With Rheumatoid Arthritis Receiving Etanercept for Up to 5 Years
Mark Lebwohl, MD; Robin Blum, MD; Eric Berkowitz, MD; Dennis Kim, MD, MPH; Ralph Zitnik, MD; Cheri Osteen, PhD; Wayne Jack Wallis, MD
Arch Dermatol. 2005;141:861-864. Abstract quote
Objective To determine the incidence of cutaneous squamous cell carcinoma (SCC) in patients with rheumatoid arthritis receiving etanercept, a tumor necrosis factor antagonist, for up to 5 years.
Design An etanercept clinical trials’ database and an etanercept postmarketing surveillance database were retrospectively analyzed for the incidence of SCC.
Setting Patients enrolled in clinical trials of etanercept were from private and institutional practices. The postmarketing database comprised reports from postmarketing trials and solicited and spontaneous reports.
Patients A total of 1442 patients with rheumatoid arthritis with 4257 patient-years of etanercept exposure (median exposure, 3.7 years) are included in the clinical trials’ database. More than 125 000 patients with more than 250 000 patient-years of etanercept exposure are included in the etanercept postmarketing database.
Interventions Most patients enrolled in clinical trials of etanercept received a dosage of 25 mg of etanercept subcutaneously twice weekly for most of the time they received etanercept therapy.
Results Only 4 cases of SCC were observed in the etanercept clinical trials’ database, an incidence that compares favorably with the expected incidences based on general population data from Arizona (13.1) and Minnesota (5.9). Similarly, few cases of SCC (1 per 10 000 patient-years) have been reported during postmarketing surveillance of etanercept therapy.
Conclusion In patients with rheumatoid arthritis, etanercept use of up to 5 years does not seem to be associated with an increase in the incidence of cutaneous SCC.
Low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis.
Allergy, Immunology and Rheumatology, Emory University School of Medicine, Atlanta, Georgia 30303, USA.
Arthritis Rheum 2001 Oct;45(5):462-7 Abstract quote
It is known and has been repeatedly demonstrated that low doses of prednisone or prednisolone (10 mg daily or 5 mg bid) will control most of the inflammatory features of early polyarticular rheumatoid arthritis (Table 2). Also, low doses of prednisolone are known to retard the bony damage of rheumatoid arthritis, and thus these are the original disease-modifying antirheumatic drugs.
Glucocorticoids are potent antiinflammatory and immunosuppressive agents by virtue of their repression of the genomic expression by transcriptional interference, inhibiting such proinflammatory proteins as COX-2, IL-1, IL-2, IL-6, TNFalpha, and adhesion molecules. Nature has produced an ideal antiinflammatory and immunosuppressive agent, namely glucocorticoids, and it is up to us to use it in appropriate situations (e.g., active early inflammatory polyarticular rheumatoid arthritis) and in low doses, frequently daily divided doses. Low doses of glucocorticoids (prednisone or prednisolone) accomplish everything NSAIDs or COX-2 inhibitors accomplish but with more antiinflammatory effects, fewer side effects, and much less expense. It is certainly possible (but not precisely tested) that low doses of prednisone (prednisolone) enhance the effects of other DMARDs, including anti-TNF agents. The side effects of low-dose glucocorticoids are minimal. By using concomitant calcium and vitamin D and monitoring bone status with DEXA scans, the osteopenia potential of low doses of prednisone will be minimal. The use of low-dose prednisone without NSAIDs will put the patient at very little risk for stomach ulceration and bleeding.
Peripheral blood stem cell transplantation for rheumatoid arthritis--Australian experience.
Moore J, Milliken S, David, Biggs J, Brooks P.
Department of Haematology, St. Vincent's Hospital, Darlinghurst, Australia.
J Rheumatol Suppl 2001 Oct;64:8-12 Abstract quote
Trials of high dose immunosuppression and peripheral blood stem cell transplantation (PBSCT) in patients with severe rheumatoid arthritis (RA) have now commenced based on encouraging data from case reports of patients with coexistent malignancy and animal transplant models.
Early case reports in Australia documented the potential for cure of RA in most patients receiving allogeneic or syngeneic transplants. However, the relatively high morbidity and mortality of these procedures has necessitated the use of autologous PBSCT. in accordance with international guidelines released by the EBMT/EULAR working party.
Phase I trials in autologous PBSCT have seen substantial remissions of RA in the majority of patients who had previously failed all available therapies. Recurrence of disease occurs in most patients usually within 2 years; however, the use of disease modifying agents after recurrence results in substantial amelioration of the disease, again suggesting a form of "immunomodulation." This observation raises the possibility of maintenance therapy associated with procedure to prolong responses. Other modifications of the procedure are discussed, including T cell depletion of the graft, currently the subject of a randomized trial.
The status of stem cell transplantation for rheumatoid arthritis: a rheumatologist's view.
Virginia Mason Research Center, Seattle, Washington 98101, USA.
J Rheumatol Suppl 2001 Oct;64:60-1 Abstract quote
Stem cell transplantation (SCT) for rheumatoid arthritis will only be appropriate for a very small proportion of patients--those with aggressive disease who have had inadequate responses to several disease modifying antirheumatic drug regimens, including tumor necrosis factor blockers.
The presence of biopsy proven T cell infiltrates in the synovium may be a way to improve appropriate patient selection. While there is general agreement regarding patient selection, the specifics of these criteria are not yet delineated. As for patient selection, the most appropriate SCT regimen has not yet been agreed upon and further pilot studies in this area will be required. In contrast to the above areas in which there is a distinct lack of consensus, outcome measures are better defined in RA and should include remission rate, Disease Activity Scale or American College of Rheumatology 50 (ACR 50) and ACR 70 responses, as well as longterm benefit/risk ratios (or utilities).
It would be appropriate to convene a 2-3 day conference in 1-2 years to decide on the above, after more pilot data have been developed.
Potential for cytokine and product manipulation to improve the results of autologous stem cell transplantation for rheumatoid arthritis.
Talmadge JE, Singh R, Ageitos A, Buyukberber S.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-7660, USA.
J Rheumatol Suppl 2001 Oct;64:32-8 Abstract quote
The eradication of autoreactive T cells by high dose therapy and stem cell transplantation and the resultant alterations in the immunologic network, thymic reeducation, and peripheral tolerance provide treatment mechanisms for autoimmune and inflammatory diseases.
One outcome of autologous stem cell transplantation is a significant decrease in the CD4:CD8 ratio due to a loss in CD4+ cells and a depression in T cell function. Mechanistically, the loss of T cell function is associated with an increased frequency of circulating monocytes, their expression of Fas ligand (FasL), and a high frequency of apoptotic CD4+ T cells. This suggests that activated Fas+ CD4+ lymphocytes interact with FasL+ monocytes. resulting in apoptosis, preferential deletion of CD4+ T cells, an inversion in the CD4:CD8 ratio, and depressed T cell function.
These observations suggest the potential for immune regulation using stem cell manipulation or posttransplant cytokine administration as therapeutic strategies for autoimmune/inflammatory diseases.
Intensive immunosuppression and autologous stem cell transplantation for patients with severe rheumatoid arthritis: the Leiden experience.
van Laar JM, Verburg RJ, Fibbe WE, Breedveld FC.
Department of Rheumatology, Leiden University Medical Center, The Netherlands.
J Rheumatol Suppl 2001 Oct;64:25-7 Abstract quote
Ten patients with active, destructive rheumatoid arthritis refractory to antirheumatic therapy enrolled in a study to evaluate the effects of intensive immunosuppression followed by autologous stem cell transplantation.
Intensive immunosuppression was achieved with high dose cyclophosphamide as part of the mobilization (4 g/m2) and conditioning (200 mg/kg) regimen. The autologous stem cell products were enriched for CD34+ cells to minimize the chance of reinfusing autoreactive lymphocytes. Eight patients completed all consecutive treatment steps, one patient withdrew after mobilization because of improvement, one patient was taken off study because of pulmonary embolism. The treatment appeared feasible and safe, and marked sustained clinical improvement was observed in 6 patients, 2 of whom were previously unresponsive to tumor necrosis factor blocking therapy. In 5 patients disease modifying antirheumatic drugs were successfully withdrawn after transplantation.
The treatment induced significant lymphopenia, with low levels of naive CD4+ T cells in particular, without clinical sequelae. Titers of rheumatoid factor dropped but did not normalize.
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