Clinical aspects of rheumatoid arthritis

doi:10.1016/j.pathophys.2005.07.009

Pathophysiology

Volume 12, Issue 3, October 2005, Pages 153-165

https://doi.org/10.1016/j.pathophys.2005.07.009 Get rights and content

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology affecting both articular tissues and extraarticular organs. The disease is often progressive and results in pain, stiffness, and swelling of joints culminating in significant morbidity and increased mortality. This chapter discusses the epidemiology, possible etiology, clinical manifestations, diagnostic approach and treatment options of RA.

Introduction

Rheumatoid arthritis is a chronic, systemic, inflammatory disorder of unknown etiology that primarily involves the joints but can also cause multiple extra-articular manifestations. RA is the most common autoimmune disease, affecting 1–1.5% of the population worldwide [1], [2], [3], [4], [5]. Rheumatoid arthritis (RA) is characterized by synovitis and autoantibody formation (RF). The hallmark feature of the disease is persistent symmetric polyarthritis (synovitis) that affects the hands, wrists and feet, although almost all diarthrodial joints may become involved. In addition to articular manifestations, systemic involvement may cause constitutional symptoms (such as weight loss, low-grade fever, malaise), rheumatoid nodules, serositis and vasculitis. The severity of RA may fluctuate over time, but chronic RA most commonly results in the progressive development of various degrees of joint destruction, deformity, significant decline in functional status and a premature death [6], [7].

Section snippets

Epidemiology

RA is one of the many chronic autoimmune diseases that predominates in women. The ratio of female to male patients is approximately 2–4:1 [8]. The basis of the gender differences is not known but presumably is related to effects of the hormonal milieu on immune function. Throughout the world, ethnic groups like the North American Pima Indians and southeast Alaskan Indians have a much higher incidence of RA [8]. The incidence of RA rises dramatically during adulthood and peaks in individuals

Etiology

Although the etiology remains a mystery, several studies suggest environmental and genetic factors are responsible. Aho et al. showed the most compelling example for both by finding a 30% concordance in monozygotic twins, compared to 5% in fraternal twins and first degree relatives [10]. Environmental factors must be related to RA development otherwise monozygotic twins would have a 100% concordance. A recognized RA genetic risk factor is the presence of the HLA-DR4 or HLA-DRB1 class II MHC

Pathophysiology

The role of the mediators of inflammation, cytokines, growth factors, chemokines, adhesion molecules and matrix metalloproteinases (MMPs) has not been clearly defined in the pathogenesis of RA. These substances appear to be involved in attracting and activating immune cells and contributing to the activation, proliferation and phenotypic transformation of synoviocytes into pannus. Pannus behaves similar to a locally invasive tumor by invading and eroding articular cartilage, subchondral bone,

General

The initial symptoms of RA (frequently articular) typically can present one of two ways; with a slow insidious onset or an explosive sudden onset. The 55–65% of cases begin insidiously, over weeks to months [21]. The 8–15% of patients have an acute onset of symptoms that peak within a few days. In some individuals, fatigue, malaise, puffy hands, diffuse musculoskeletal pains or morning stiffness may be the first nonspecific complaints, with synovitis occurring later. Asymmetric presentations

The hand

Symmetric involvement of the hands is the hallmark of RA, with swelling of the MCP and PIP joints. MCP involvement, with the development of palmar subluxation and ulnar deviation, is more characteristic of progressive RA. Synovitis within the MCP joints weakens the dorsal and radial structures and loosens the collateral ligaments. This loosening allows reducible (not fixed) radial deviation of the wrists and associated ulnar deviation of the fingers.

Three additional PIP deformities can occur as

Extra-articular manifestations

The number and severity of extra-articular features vary with the duration and severity of the disease. Extra-articular manifestations of RA are associated with the observed excessive mortality [30], [31], [32].

Differential diagnosis

Other diseases must be considered which appear similar to RA [58] include:

1.
Spondyloarthropathies:
- •
  ankylosing spondylitis,
- •
  enteric infections,
- •
  inflammatory bowel disease,
- •
  psoriatic arthritis,
- •
  reiter's arthritis,
- •
  whipple's disease;
2.
Infectious causes:
- •
  acute rheumatic fever,
- •
  bacterial endocarditis,
- •
  gonococcal arthritis,
- •
  lyme disease,
- •
  viral infections (parvo-B 19, HIV, Hep.C);
3.
Metabolic and endocrinecauses:
- •
  arthritis of thyroid disease,
- •
  gout,
- •
  hemochromotosis,
- •
  hemoglobinpathies,
- •
  pseudogout;
4.
Connective tissue diseases:
- •

Laboratory work up

Serum protein abnormalities are often present. Rheumatoid factor (RF), an antibody directed against the Fc fragment of immunoglobulin G (IgG), is present in the sera of more than 75% of patients. High titers of RF are commonly associated with severe rheumatoid disease. Antinuclear antibodies are demonstrable in 20% of patients, though their titers are lower in RA than in SLE. However, the specificity of RF for RA is 74–98%.

The amount of rheumatoid factor in blood can be measured as follows.

Imaging studies

Plain radiography of affected joints is essential in the evaluation of patients. The earliest changes occur in the wrists or feet and consist of soft-tissue swelling and juxta-articular demineralization. Later, the diagnostic changes of uniform joint-space narrowing are evident, and erosions develop. The erosions are often first evident at the fifth metatarsal head or ulnar styloid and at the juxta-articular margins, where the bony surface is not protected by cartilage. These changes frequently

MRI

Currently, magnetic resonance imaging is the best imaging modality to detect erosions. Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI depicts soft-tissue changes and damage to cartilage and bone even better and at an earlier stage than does computed tomography. However, its cost precludes its widespread use.

Ultrasound

Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA. Doppler ultrasound can aid in the initial diagnosis of RA even in the presence of minimal radiographic data on presentation. PDUS may be reliable for monitoring inflammatory activity in the joint. QUS, which is used for osteoporosis, has been used to detect bone loss in fingers, which may prove to be a good indicator of early RA. US is a sensitive method for assessing

Disease outcome and functional capacity in rheumatoid arthritis

RA is the most common form of inflammatory arthritis, and causes a substantial cost, disability, and lost work productivity [65]. Physical job demands, low functional capacity, old age, and low education may predict work disability and eventual premature death in patients with RA [6], [7].

Depression in RA has been linked to low levels of physical activity, functional disability, pain, fatigue, poor perception of health, increased use of health services, social stress, low level of education,

Management of rheumatoid arthritis

The management of the patient with RA is directed at preserving joint integrity and function as well as preventing extra-articular manifestations. All affected joints may become destroyed thus; every patient with established disease should receive treatment as early as possible. The management of patients with RA is with disease-modifying anti-rheumatic drugs (DMARDS) and anticytokine therapies. While the treatment of RA has evolved from the empiric (use of injected gold salts) to targeted

Summary

Rheumatoid arthritis (RA) is a chronic systemic inflammatory polyarthritis of unknown etiology. In addition to the joint manifestations, RA is an illness, which affects most organ systems with significant morbidity and mortality. However, the new medications and treatment regimens may decrease the observed morbidity and mortality from this disease.

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The lower reference limits for creatine kinase (CK) in included patients with RA were somewhat lower than the corresponding health associated reference limits. As CK correlates with muscle mass [24] and patients with RA are at risk of developing muscle atrophy [25,26], low concentrations of CK are not unexpected. The estimated reference limits indicate how much lower concentrations to expect.
Population based reference intervals are fundamental for interpreting results for quantitative laboratory tests. In patients with a specific chronic disorder, however, results of various tests may regularly be different than in healthy individuals. Health-associated reference intervals may therefore have limited value in such patients. Instead, disease-associated reference intervals may be useful, as they describe the results distribution in populations resembling the specific patients. Few disease-associated reference intervals are available in the literature. The aim of this study was to estimate reference intervals for common laboratory tests for patient populations with rheumatoid arthritis, Crohn’s disease or ulcerative colitis without significant comorbidity, using a novel algorithm.
Laboratory test results and hospital discharge diagnoses were collected for relevant patients. An algorithm was developed to identify discharge diagnoses significantly associated with high or low results for specific tests. After excluding patients with such diagnoses, reference intervals were estimated, representing results distributions in patients with each of the specific chronic disorders, but without significant comorbidity.
Disease-associated reference intervals were estimated for 20 common laboratory tests. Most of the estimated reference limits were significantly different from corresponding health-associated reference limits. Thirty percent of the estimated reference intervals were different from estimates based on crude patient populations, indicating that the algorithm applied managed to exclude patients with relevant comorbidity.
Disease-associated reference intervals could be estimated for a number of tests in patients with rheumatoid arthritis, ulcerative colitis or Crohn’s disease using a highly automated algorithm based on routinely recorded patient data.
Evaluating the relationship between dietary intake with inflammatory factors, lipid profile and clinical symptoms in patients with rheumatoid arthritis
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Rheumatoid arthritis (RA) is one of the most common life-threatening and associated with inflammation. The aim of this study was to evaluate the relation between dietary intake, inflammatory factors, lipid profile, medication and clinical outcomes in patients with rheumatoid arthritis.
This cross-sectional study were conducted in 72 patients with RA that referred to Rheumatology Clinic, Urmia, Iran. After describing the study and obtaining patient consent, fasting blood samples were collected from all participants in start stage, Nuclear Factor-Kappa B (NF-KB), Oxidized Low-Density Lipoprotein (Ox-LDL), lipid profile and clinical symptoms were record in participants. Also, Data on dietary intake and physical activity were collected with relevant questionnaires.
There was a positive significant relation between energy intakes and low-density lipoprotein Cholesterol (LDL-C) (R = 0.855, P = 0.023), carbohydrate intake with total cholesterol (R = 0.297, P = 0.045), carbohydrate intake and NF-kB (R = 0.292, P = 0.017), fat intakes and Ox-LDL (R = 0.321, P = 0.027), prednisolone and Triglyceride (TG) (R = 0.378, P = 0.016), calcium supplement, folic acid and High-Density Lipoprotein Cholesterol (HDL-C) (R = 0.259, R = 0.34, R = 0.355, P = 0.09 respectively). In addition, the correlation between carbohydrate and energy intakes with HDL-C were negative significant (R = −0.355, P = 0.09 and R = −0.259, P = 0.034). SJC, Tender Joint Count (TJC), Erythrocyte Sedimentation Rate (ESR) and VAS were related to DAS28 and other variables shown no relation with DAS28.
There are many factors affecting the clinical symptoms of patients with RA that attention to nutritional and medicinal factors can have a significant role in the clinical symptoms and complications of these patients.
Stability, solution structure and X-ray crystallography of a copper (II) diamide complex
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RA often affects pairs of joints (both hands, both feet, etc) and can affect more than one joint. Over time, other joints can be affected such as shoulders, elbows, knees, feet, and ankles [6–8]. The use of drug therapy for RA is mainly for the relief of pain, the inhibition of inflammation and the restoration of normal immune mechanisms [9], as well as, multidisciplinary health care to preserve functional capacity of joints [10].
It has been shown that the inflammation associated with rheumatoid arthritis can be reduced using copper complexes. In order to improve the bioavailability of copper and hence efficacy, 3-(2-aminoacetamido)-N-(pyridin-2-ylmethyl)propanamide, H₂(5 6 5)NH₂, was designed as a potential chelator of copper. Solution equilibrium measurements show that the [Cu(LH_-2)] species predominates at physiological pH and blood plasma speciation calculations predict that this ligand is able to mobilise Cu(II) in vivo. A structural study of the Cu(II)/H₂(5 6 5)NH₂ system was conducted in the solid and solution state using Uv–Vis, CD, ¹H NMR and EPR spectroscopy and single crystal X-ray crystallography. The result indicate that the structure of [Cu(H₂(5 6 5)NH₂)H_-2] in the solid and solution state are similar and confirm that, the metal binds to the pyridine nitrogen, the two amide nitrogens and the terminal amino group in a distorted square planar geometry.
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Rheumatoid arthritis (RA) is a common debilitating autoimmune disease that is characterized by progressive joint disorder, significant pain and functional disability. Although the etiology of RA remains a mystery, an interlinked role of genetic, environmental and immunologic factors has been suggested [1]. Endothelial dysfunction in RA has been documented [2,3].
This work aimed to evaluate serum pentraxin 3 (PTX3) levels in rheumatoid arthritis (RA) patients and to study the association with the disease activity.
Sixty RA patients and 26 matched controls were included. In patients, clinical examination was performed and disease activity score (DAS28) assessed. Serum PTX3, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured.
The mean age of the patients was 54.9 ± 11.7 years, and the median (Min–Max) of disease duration was 24 (3.96–60) months and 91.7% were females. The mean DAS28 was 4.16 ± 1.77, the ESR was 38.6 ± 23.03 mm/1st h, CRP was 14.9 ± 8.6 mg/l, RF was 49.6 ± 28.1 IU/ml and the median anti-CCP was 375. Serum PTX3 level was significantly higher in RA patients (2.82 ± 0.48 pg/ml) compared to controls (2.56 ± 0.29 pg/ml) (p = 0.003). There was a significant difference in serum PTX3 level according to the disease activity: remission (2.49 ± 0.16 pg/ml), low (2.61 ± 0.33 pg/ml), moderate (2.90 ± 0.53 pg/ml) and high (3.01 ± 0.51 pg/ml) (p = 0.016). There was a significant correlation between serum PTX3 level with disease activity (r = 0.39, p = 0.002) and CRP (r = 0.49, p < 0.001). There was no significant correlation between serum PTX3 level and the RF (r = 0.25, p = 0.054), anti-CCP (r = 0.18, p = 0.17) and ESR (r = 0.09, p = 0.51). PTX3 and CRP showed a good sensitivity and specificity in predicting RA disease (p = 0.006 and p < 0.001, respectively).
PTX3 can be considered as a marker of a positive acute phase response and may serve as a potential novel biomarker for detecting RA activity.
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Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by joint inflammation, bone and cartilage erosion. The use of glucocorticoids in the treatment of RA is hampered by significant side effects induced by their unfavorable pharmacokinetics. Delivering glucocorticoids by means of nanotechnologies is promising but the encapsulation of highly crystalline and poorly water-soluble drugs results in poor loading and low stability. We report here the design of 130 nm nanoparticles made of solely dexamethasone palmitate, stabilized by polyethylene glycol-linked phospholipids displaying a negative zeta potential (−55 mV), high entrapment efficiency and stability over 21 days under storage at 4 °C. X ray diffraction showed no crystallization of the drug. When incubated in serum, nanoparticles released free dexamethasone which explains the in vitro anti-inflammatory effect on LPS-activated RAW 264.7 macrophages. Moreover, we demonstrate in a murine collagen-induced arthritis model the improved therapeutic efficacy of these nanoparticles. Their passive accumulation in arthritic joints leads to disease remission and recovery of the joint structure at a dose of 1 mg/kg dexamethasone, without any adverse effects. Dexamethasone palmitate nanoparticles are promising in the treatment of inflammation in rheumatoid arthritis with a very significant difference occurring at the late stage of inflammation allowing to prevent the progression of the disease.
Nodular rheumatoid arthritis (RA): A distinct disease subtype, initiated by cadmium inhalation inducing pulmonary nodule formation and subsequent RA–associated autoantibody generation
2019, Medical Hypotheses
Citation Excerpt :
Rheumatoid arthritis (RA) is a relatively contemporary disease having been first described in early 19th century Paris [1]. Florid classical RA is a characteristic disease with the development of ulnar deviation, swan neck deformities and subcutaneous nodules [2]. However, even in untreated disease, these features do not always develop, suggesting distinct RA subtypes.
Nodular rheumatoid arthritis (RA) patients have raised rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA) levels, and are more likely to smoke than RA patients without nodules. Subcutaneous and pulmonary rheumatoid nodules (granulomas) frequently co–exist. Pulmonary rheumatoid nodules develop prior to RA development and have the immunological machinery to generate RF and ACPAs. Pulmonary granulomas have been observed in animal models exposed to cadmium (Cd) inhalation. Cigarette smoke increases pulmonary Cd exposure. It has been suggested that dust and cigarette smoke co–exposure increases localised pulmonary Cd adsorption. We hypothesise that subcutaneous nodular RA represents a distinct disease subtype induced by pulmonary rheumatoid nodule formation and the generation of high levels of RA associated autoantibodies initiated by Cd inhalation via cigarette smoke.
Cohorts of RA patients attending rheumatology clinics in Cornwall, UK (total n = 504) were studied to determine the prevalence of nodular RA, with matched analysis (age, gender and social class) to compare urinary Cd, RF and ACPA levels stratifying for nodular disease and smoking.
In cohort 1 45/303 (14.9%) of the RA patients under regular follow up had nodular disease. Of the RA smokers, 30/155 (19%) were nodular and of the RA non–smokers 15/148 (10%) were nodular. Smoking was significantly associated with nodular RA, odds ratio (OR) = 2.48 95% confidence interval (CI) 1.26–4.88, p = 0.008. Raised urinary Cd levels were significantly associated with nodular RA in non–dust exposed individuals, OR 2.26 (95% CI 1.08–4.73), p = 0.03 compared to dust exposed individuals, OR 0.78 (95% CI 0.35–1.76), p = 0.557, despite fewer pack years (py) at diagnosis (16 vs 20 py). Nodular RA smokers had significantly raised RF levels compared to RA smokers without nodular disease (median RF 171.5 (interquartile range (IQR) 48–394) vs median RF 31.7 (IQR 10.3–170.3), p < 0.00001). RF positivity was significantly more prevalent in nodular RA smokers compared to RA smokers without nodular disease (84/89 (94%) vs. 141/199 (71%), OR = 6.9 (95% CI 2.66–17.91), p < 0.00001). ACPA levels were also significantly raised in nodular smokers compared to non–nodular smokers (median ACPA 250 (IQR 145–426) vs 116 (1–257.5), p < 0.00001), as were ACPA positivity rates (83/89 (93%) vs 123/191 (64%), OR = 7.65 (95% CI 3.17–18.4), p < 0.0001).
These pilot results support the hypothesis that nodular RA represents a distinct disease subtype initiated by cadmium inhalation, which we suggest induces pulmonary rheumatoid nodule formation and generation of RA–associated autoantibodies.

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Clinical aspects of rheumatoid arthritis

Abstract

Introduction

Section snippets

Epidemiology

Etiology

Pathophysiology

General

The hand

Extra-articular manifestations

Differential diagnosis

Laboratory work up

Imaging studies

MRI

Ultrasound

Disease outcome and functional capacity in rheumatoid arthritis

Management of rheumatoid arthritis

Summary

J. Chronic. Dis.

J. Chronic. Dis.

Baillieres Clin. Rheumatol.

Am. J. Med.

Clin. Immunol.

Semin. Arthritis Rheum.

Lancet

The epidemiology of rheumatoid arthritis: a review. II. Incidence and diagnostic criteria

Bull. Rheum. Dis.

A genetic study of rheumatoid arthritis and rheumatoid factor in Blackfeet and Pima Indians

Arthritis Rheum.

Rheumatoid arthritis in adults

Vital Health Stat. 1

Rheumatoid arthritis in Hiroshima and Nagasaki, Japan. Prevalence, incidence, and clinical characteristics

Arthritis Rheum.

Survival and cause of death in rheumatoid arthritis: a 25-year prospective follow-up

J. Rheumatol.

Survival in rheumatoid arthritis

Arthritis Rheum.

Twin concordance rates for rheumatoid arthritis: results from a nationwide study

Br. J. Rheumatol.

Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred

Genet. Epidemiol.

Association of the B-cell alloantigen DRw4 with rheumatoid arthritis

N. Engl. J. Med.

Genetics of rheumatoid arthritis: confronting complexity

Arthritis Res.

Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope

Arthritis Rheum.

Antibodies to synthetic peptides from Epstein–Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera

J. Rheumatol.

Influence of previous exposure to human parvovirus B19 infection in explaining susceptibility to rheumatoid arthritis: an analysis of disease discordant twin pairs

Ann. Rheum. Dis.

Autoantibodies and antibodies to microorganisms in rheumatoid arthritis: comparison of histocompatible siblings

J. Rheumatol.

Does diet have a role in the aetiology of rheumatoid arthritis?

Proc. Nutr. Soc.

Mortality in rheumatoid disease

J. Insur. Med.

Death rates and causes of death in patients with rheumatoid arthritis: a population-based study

Scand. J. Rheumatol.

Early rheumatoid disease. I. Onset.

Ann. Rheum. Dis.

Early rheumatoid disease. II. Patterns of joint involvement

Ann. Rheum. Dis.

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum.

Prevalence of mutilans-like hand deformities in patients with seropositive rheumatoid arthritis. A prospective 20-year study

Scand. J. Rheumatol.

Chronic triangular fibrocartilage complex tears with distal radioulna joint instability: A new method of triangular fibrocartilage complex reconstruction

J. Orthop. Surg. (Hong Kong)

Stress fractures of the distal fibula presenting as monarticular flares in patients with rheumatoid arthritis

Arthritis Rheum.

Achilles tendon rupture owing to rheumatoid disease. Case report with a nine-year follow-up

JAMA

Bilateral midline fixation of cricoarytenoid joints as a serious medical emergency

JAMA