Showing posts with label arthritis. Show all posts
Showing posts with label arthritis. Show all posts

Saturday, April 7, 2018

HCV Screening: Important for Rheumatology Patients

HCV Screening: Important for Rheumatology Patients
Cassandra Calabrese, DO, shares her experiences
by Cassandra Calabrese, DO
April 07, 2018
I spent this past week seeing hepatitis C virus (HCV) patients with our hepatologists. Being a rheumatologist, I was looking forward to seeing extrahepatic manifestations of HCV that we read about in textbooks -- cryoglobulinemic vasculitis, sicca syndrome, porphyria cutanea tarda, and many others. I suppose I should not be surprised that the week passed without seeing a single one of these.

While a wide array of extrahepatic manifestations, including may rheumatologic ones, will occur in 40%-70% of chronic HCV patients, the advent of direct-acting antivirals (DAA) has changed HCV outcomes, such that I do not think we will be seeing these cases much longer...

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Other Conditions That May Be Related To HCV

Saturday, November 11, 2017

Psoriasis tied to higher risk of serious liver disease

Psoriasis tied to higher risk of serious liver disease
Last Updated: 2017-11-10
By Lisa Rapaport

(Reuters Health) - People with chronic inflammatory disorders like psoriasis and rheumatoid arthritis may have an increased risk of developing serious liver damage, a recent study suggests.

These inflammatory disorders are often treated with methotrexate, a medication linked to an increased risk of liver disease. For the current study, researchers followed more than 1 million people for an average of six years to see how having conditions like psoriasis or rheumatoid arthritis - and taking methotrexate - influenced the odds of developing serious liver disorders.

Compared to people without chronic inflammatory diseases, people with psoriasis were 37% more likely to develop liver disorders. When psoriasis patients took methotrexate, they had roughly twice the odds of liver damage.

With psoriatic arthritis, the increased risk of liver disease was 38% without drug therapy and 67% with methotrexate. For rheumatoid arthritis, there was no increased risk of liver disease when people took methotrexate, but when they didn't they had 49% higher odds of liver damage.


J Invest Dermatol 2017.

Wednesday, October 18, 2017

Healio Rheumatology - Hepatitis C and the Rheumatologist

Healio Rheumatology

Hepatitis C and the Rheumatologist: Our Role in the Quest for Global Eradication of HCV
Healio Rheumatology, October 2017
Leonard H. Calabrese, DO
I am pleased to have Healio Rheumatology focus this issue’s Cover Story on the intersection of viral hepatitis and rheumatology, as this is a subject both near to my heart as well as one of great importance to many patients. Our esteemed sources enlighten us on many aspects of the impact of viral hepatitis and rheumatic diseases from not only from the perspective of these viruses as etiologies for many rheumatic syndromes, but also, and far more important, from a prevalence perspective – the impact of chronic viral hepatitis, both hepatitis B and C, as comorbidities.

Educating Rheumatologists on Hepatic Associations With Rheumatic Diseases
Healio Rheumatology, October 2017
Historic advances have been occurring in hepatitis C therapy during the last decade. This once difficult-to-treat chronic infection is essentially curable with direct-acting antiviral therapies. For hepatitis B, a wave of biologic therapies is changing the landscape and offering hepatologists, gastroenterologists and infectious diseases clinicians a host of options to manage patients.

Fibromyalgia: Few New Treatments, But Understanding Continues to Grow
Healio Rheumatology, October 2017
Efforts to better understand and treat fibromyalgia are ongoing and multifaceted, with an increased emphasis on both drug and non-drug treatments during the past 20…

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HCV Advocate - Extrahepatic Manifestations of Hepatitis C
Oct 5 - Diabetes

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Rheumatologic manifestations of hepatitis C virus - is included in this collection of articles.

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Categorized article directory on the extrahepatic manifestations of hepatitis C.

Friday, July 14, 2017

Extrahepatic manifestations of HCV & Treatment

If you are interested in reading full text articles about the treatment and management of HCV I highly suggest you follow Henry E. Chang on Twitter.

Latest Tweets By @HenryEChang on the extrahepatic manifestations of HCV.

July 14, 2017
Extrahepatic manifestations of HCV: The role of direct acting antivirals
María Laura Polo and *Natalia Laufer
Expert Review of Anti-infective Therapy DOI: 10.1080/14787210.2017.1354697

Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations.

This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions.  Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
Link - Download Full Text Article.......

Clinics in Liver Disease, Volume 21, Issue 3

Chronic Hepatitis C Virus Infection and Depression
Luigi Elio Adinolfi, Riccardo Nevola, Luca Rinaldi, Ciro Romano, Mauro Giordano

HCV Depression Quality of life


Depression is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection reported in one-third of patients.

The prevalence of depression in patients with HCV has been estimated to be 1.5 to 4.0 times higher than that observed in the general population.

Direct HCV neuro-invasion, induction of local and systemic inflammation, neurotransmission, and metabolic derangements are the hypothesized pathogenic mechanisms of depression.

Depression considerably impacts health-related quality of life of HCV-positive patients.

Clearance of HCV by antiviral treatments is associated with an improvement of both depression and quality of life.
Link - Download Full Text PDF

Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty

Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor


Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
Link - Download Full Text PDF

Neurologic manifestations of hepatitis C virus infection
Sentia Iriana, MD, Michael P. Curry, MD, Nezam H. Afdhal, MD, DSc

Hepatitis C Fatigue Neurocognition MR spectroscopy Interferon Ledipasvir/sofosbuvir Cerebrovascular disease

The extrahepatic manifestations of hepatitis C virus (HCV) in the brain include neurocognitive dysfunction, which is manifested by subtle changes in memory, attention, and processing speed.

Neurocognitive defects are independent of the histologic stage of disease and may be induced by a direct effect of HCV on microglial cells or mediated by systemic cytokines crossing the blood-brain barrier.

Magnetic resonance spectroscopy demonstrates abnormal metabolism in basal ganglia and prefrontal and frontal cortex, which has been associated with fatigue and abnormal neurocognitive testing. Interferon and direct-acting antiviral therapy can improve cerebral metabolism and neurocognition if a sustained virologic response is obtained.

Cerebrovascular events and mortality are increased in patients with HCV and may be through an increased risk of carotid artery disease and plaque formation.
Link - Full Text PDF Article

Rheumatologic manifestations of hepatitis C virus
Patrice Cacoub, Cloé Comarmond, Anne Claire Desbois, David Saadoun

Hepatitis C (HCV) Rheumatic disorders Arthritis Vasculitis Arthralgia Sicca syndrome

Main rheumatologic manifestations reported with hepatitis C virus (HCV) chronic infection include arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.

Immunologic factors predisposing to developsuch manifestations include stimulation of B cells, expansion of B-cell–producing immunoglobulin M with rheumatoid factor activity and of clonal marginal zone, like B cells, and a decrease of regulatory T cells.

The treatment of HCV infection with interferon alpha has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders.

New oral interferon-free combinations now offer an opportunity for patients with HCV extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a high efficacy rate and a low risk of side effects.
Link - Full Text PDF Download

Other EHM of HCV infection (pulmonary, idiopathic thrombocytopenic purpura, nondiabetes endocrine disorders
Daniel Segna, Jean-François DuFour

Hepatitis C Extrahepatic manifestations Pulmonary Endocrine Idiopathic thrombocytopenic purpura


Hepatitis C Virus (HCV) infection may increase the risk for obstructive, interstitial, and vascular lung disease, lung cancer, and mortality in HCV-infected lung transplant recipients.

HCV infection may increase the risk of idiopathic thrombocytopenic purpura, nonresponse to corticosteroids during the treatment, and higher rates of splenectomy.

HCV infection may increase the risk of autoimmune thyroiditis, infertility, growth hormone and adrenal deficiency, osteoporosis, and low-trauma fractures.

Targeted prospective cohorts may confirm these results mostly obtained from small casecontrol studies with different study populations and low level of evidence.
Link - Full Text PDF Download

Hepatitis C Virus–Associated Non-Hodgkin Lymphomas
Gabriele Pozzato, Cesare Mazzaro, Valter Gattei

Hepatitis C virus Marginal zone lymphoma Non-Hodgkin lymphoma Direct antiviral agents

Eradication of hepatitis C virus (HCV) in indolent non-Hodgkin lymphomas (NHLs), especially in marginal zone lymphomas(MZLs), determines the regression of the hematological disorder in a significant fraction of cases.

Because direct antiviral agents (DAAs) show an excellent profile in terms of efficacy, safety, and rapid onset of action, these drugs can be used in any clinical situation and the presence of any comorbidities.

To avoid the progression of the NHL, despite HCV eradication, antiviral therapy should be provided as soon as the viral infection is discovered; before that, the chronic antigenic stimulation determines the irreversible proliferation of neoplastic B cells.
Link - Full Text PDF Download

Dermatologic manifestations of chronic hepatitis C
Mehmet Sayiner, Pegah Golabi, Freba Farhat, Zobair M. Younossi

Hepatitis C Extrahepatic manifestation Dermatologic manifestation Cryoglobulinemia Porphyria Lichen planus

HCV infection is associated with several dermatologic diseases, such as symptomatic mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, and necrolytic acral erythema.

Most of the dermatologic manifestations may be caused by immune complexes. In the interferon and ribavirin era, treatment was associated with dermatologic side effects.

The new generation of interferon-free and ribavirin-free anti-HCV regimens is devoid of dermatologic side effects.
Link - Full Text PDF Download

Hepatitis C Infection - A systematic disease
Zobair M. Younossi
Hepatitis C virus Hepatic complications Extrahepatic complications

It is critical to recognize that hepatitis C virus (HCV) infection is a multifaceted systemic disease with both hepatic and extrahepatic complications.

The comprehensive burden of HCV should not only include its clinical burden, but also its burden on the economic and patient-reported outcomes.

It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden, and understand the full benefit of curing HCV for the patient and the society.
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Thank you Henry E. Chang

Friday, June 30, 2017

Original Article The clinical roles of rheumatoid factor in the treatment of chronic hepatitis C infection

Int J Clin Exp Med 2017;10(6):9456-9462 /ISSN:1940-5901/IJCEM0049611

Original Article The clinical roles of rheumatoid factor in the treatment of chronic hepatitis C infection
Wei-Ming Chen1,2,3*, Kao-Chi Chang1*, Ko-Ming Lin2,3,4, Kuo-Liang Wei1,3, Pey-Jium Chang2, Te-Sheng Chang1,2,3, Chein-Heng Shen1, Shui-Yi Tung1,3

Received January 24, 2017; Accepted April 28, 2017; Epub June 15, 2017; Published June 30, 2017

Download Full Text Article

Abstract: Objective:
The hepatitis C virus infection is associated with arthritis. However, the clinical roles of the rheumatoid factor in patients who received anti-viral treatment are not as clear.

Methods: To identify the association between the rheumatoid factor and the treatment response in hepatitis C virus infected patients, we enrolled patients who received anti-viral treatment with peg-interferon plus weight-based ribavirin according to response guided therapy. Patients who had a mix type hepatitis C infection, any autoimmune diseases, hepatitis B co-infection or intolerance to the side effects of therapy were excluded. Patients were divided into a rheumatoid factor (RF) positive (>20 IU/ml) group and a rheumatoid negative group. The patient’s characteristics, treatment response, dynamic changing of the rheumatoid factor and factors influenced the sustained virus response (SVR) of therapy, which were analyzed.

Results: A total of 271 patients completed the anti-viral treatment and analysis. The positive rate of the rheumatoid factor is 47.23% (128/271). In the RF positive group, the SVR rate was 82.8%, 71.0%, 96.6% for overall, genotype 1 infected, and non-genotype 1 infected patients, respectively. In the RF negative group, the SVR rate was 77.6%, 66.7%, 91.9% for overall, genotype 1 infected, and non-genotype 1 infected patients, respectively. There is a trend toward a higher SVR rate in RF positive patients, but no statistical difference was noted. In RF positive patients who achieved SVR, the RF values reduced significantly (56.4±78.0 vs. 39.4±39.6, P<0.001) after treatment but not in the non-SVR group (43.8±25.9 vs. 31.7±13.5, P=0.074). In the RF negative group, 37.8% and 34.4% of the patients’ RF became positive after treatment in the SVR group and in the non-SVR group. A lower virus load (<800,000 copies/ml), non-genotype 1 infection, alanine aminotransferase (ALT) rapid normalization, rapid viral response (RVR) and complete early viral response (cEVR) are significant predictive factors associated with SVR. The present or dynamic change of the rheumatoid factor cannot predict the effect of the treatment response.

Conclusions: The rheumatoid factor was positive in 47% of the chronic hepatitis C virus infected patients. In the RF positive group, the treatment response was better but not statistically significant. After treatment, the RF value was significantly reduced in cured patients.
Continue reading....

Recommended Reading
An Overview of Extrahepatic Manifestations of Hepatitis
A patient friendly fact sheet explaining conditions associated with HCV including symptoms.
The hepatitis C virus mainly affects the liver, but there are many other conditions that are associated with hepatitis C.  Extrahepatic manifestation means diseases or conditions that affect organs other than the liver.  Extrahepatic manifestations of hepatitis C can be found in the skin, eyes, joints, immune system, nervous system and kidneys.  Some of these conditions – cryoglobulinemia, for example – are somewhat more common and well documented, while others are infrequent or their association with hepatitis C has not yet been proven.

Recently published in Journal of Advanced Research is a nice collection of review articles on the extrahepatic manifestations of HCV.
Volume 8, Issue 2, March 2017, Pages 85–87

In The News
Lower Risk of Hep C Extrahepatic Manifestations With Sustained Virological Response
Patients who achieved a sustained virological response (SVR) to interferon-based antiviral therapy for hepatitis C virus (HCV) had a reduced risk of extrahepatic manifestations, according to a retrospective cohort study.

Monday, April 3, 2017

Painful Joints?

Painful Joints?
Early Treatment for Rheumatoid Arthritis Is Key

Painful, swollen, and stiff joints can be a sign of arthritis. Rheumatoid arthritis is one of the most common forms. The pain and stiffness can interfere with your life at home and at work. For some people, the disease is mild, but for others it can be disabling. Scientists continue to search for the cause of this disease and for ways to improve treatment.

Arthritis is an inflammation of the joints. There are over 100 types of arthritis. While their symptoms can be similar, their underlying causes vary. Osteoarthritis is the most common type of arthritis. It’s far more common than rheumatoid arthritis. Osteoarthritis is caused by wear and tear on your joints. In rheumatoid arthritis, your immune system—which normally helps protect your body from infection and disease—starts attacking your joint tissues.

Anyone can get rheumatoid arthritis. The disease most often begins in middle age or later. But it can occur at any age. Even children sometimes get a similar form of arthritis. Some types of arthritis affect one joint at a time, but rheumatoid arthritis can affect your whole body.

It’s important to get the correct diagnosis because each form of arthritis needs to be treated differently. To diagnose rheumatoid arthritis, doctors use medical history, physical exams, X-rays, and lab tests. There’s no single test for the disease. It’s not easy to diagnose.

“The joint swelling in rheumatoid arthritis is squishy, and very different from the hard bony enlargement of the finger joints that is sometime present in osteoarthritis,” explains Dr. Michael M. Ward, who oversees rheumatoid arthritis research at NIH.

Your joints may appear red and feel warm. Pain and stiffness may be worse after you wake up or have been resting for a long time. Over time, your immune system damages the tough, flexible tissue (cartilage) that lines joints. This damage can be severe and deform your joints.

Scientists don’t know exactly what causes rheumatoid arthritis. It’s likely a combination of genetics and environmental triggers, such as tobacco smoke or viruses. Hormones may also play a role. More women are diagnosed with rheumatoid arthritis than men. The disease sometimes improves during pregnancy or flares up after pregnancy.

What scientists do know is that the damage is caused by the immune system gone awry. The body’s defense system mistakenly attacks the membrane that lines joints, such as in the wrists, fingers, and toes. Joints in the neck, knees, hips, ankles, and elsewhere can also be affected.

“The immune system is supposed to be something that does good things for you,” says Dr. M. Kristen Demoruelle, an NIH-funded arthritis expert at the University of Colorado Anschutz Medical Campus. “It’s supposed to help you fight infections. But in rheumatoid arthritis—for reasons that we don’t yet understand—the immune system gets confused and then starts to attack your joints instead.”

There’s no cure for rheumatoid arthritis. But there are effective treatments. Treatment can relieve pain, reduce joint stiffness and swelling, and prevent further joint damage.

Research advances have improved patient outcomes in the past 10 to 20 years. Doctors no longer wait to start treating a person with rheumatoid arthritis. Now, they know to begin treatment right away—before joint damage worsens. Early detection is very important to increase the chance that treatment is successful.

“If we can get you into low disease activity by 6 months and remission [no signs of the disease] by 1 year, we’ve got an incredibly good chance of the disease having a very minimal impact on your life,” says Dr. Vivian P. Bykerk, an NIH-funded arthritis researcher at the Hospital for Special Surgery in New York.

There are many different classes of drugs available. Many of the drugs, like NSAIDs (nonsteroidal anti-inflammatory drugs) and steroids, work by reducing inflammation. Such drugs may be used in combination with others that have been shown to slow joint destruction.

NIH scientists helped develop a new class of drug for rheumatoid arthritis called Janus kinase (JAK) inhibitors. These drugs work by suppressing the body’s immune response. Several years ago, the first drug in this new class was approved by FDA for moderate to severe rheumatoid arthritis. Researchers continue to investigate new types of drugs and drug combinations.

“We really have to rely on our experience. We consider the combination of signs, symptoms, and blood tests to choose the right treatment,” Bykerk explains. Once treatment for rheumatoid arthritis is underway, patients need frequent checkups. Doctors may need to try and adjust different drugs or drug combinations to find the best fit for each person. Treatments are usually required for the long term to maintain control of the disease. For some people, symptoms go on for years, even a lifetime. Sometimes after months of mild disease, symptoms can flare up again.

Bykerk also works on an NIH-supported team of scientists who are searching for more effective treatment approaches. The team analyzes joint tissue and blood samples from people with rheumatoid arthritis to better understand the genes and proteins that trigger and drive the disease. The researchers aim to learn why some people respond differently to different treatments. They also hope to one day be able to tailor treatments to each person. Other studies are exploring how long people need to be treated once the disease is under control to prevent it from returning.

Rheumatoid arthritis can affect virtually every area of your life, from work to relationships. If you have rheumatoid arthritis, there are many things you can do to help maintain your lifestyle and keep a positive outlook. Exercise helps keep your muscles healthy and strong, preserve joint mobility, and maintain flexibility. Rest helps to reduce joint inflammation, pain, and fatigue. Ask your doctor how best to balance exercise and rest for your situation.

New research advances continue to help improve quality of life for people with rheumatoid arthritis. Talk with your doctor about how to treat your joint pain and stiffness so that you can lead a full, active, and independent life.

Rheumatoid arthritis. Smolen JS, Aletaha D, McInnes IB. Lancet. 2016 Oct 22;388(10055):2023-2038. doi: 10.1016/S0140-6736(16)30173-8. Review. PMID: 27156434

Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH; National Arthritis Data Workgroup. Arthritis Rheum. 2008 Jan;58(1):15-25. doi: 10.1002/art.23177. PMID: 18163481

NIH News in Health, April 2017

Tuesday, January 14, 2014

Behind The Headlines -Could cannabis compound soothe arthritis pain?

Could cannabis compound soothe arthritis pain?

“Synthetic cannabis-like molecule developed in lab could help osteoarthritis sufferers,” reports The Daily Telegraph.

Anecdotal reports of cannabis’s ability to soothe chronic pain conditions such as osteoarthritis have been available for many years.

Aside from the obvious legal issues (cannabis is a Class B illegal drug), cannabis also carries the risk of side effects and complications such as psychosis and depression

So a compound containing the drug’s painkilling ability without its psychoactive effects could lead to useful new treatments. 

One candidate is “JWH133” a chemical that binds to and activates the cannabinoid 2 (CB2) receptor. Receptors are proteins found on the surfaces of cells. When activated receptors cause a response inside cells. The CB2 receptor is also activated by tetrahydrocannabinol (THC), the principle psychoactive constituent in cannabis. Activating the CB2 receptor is thought to relieve pain and inflammation. 

The new research found evidence that JWH133 relieves pain in a rat model of arthritis. Importantly, the JWH133 compound is selective for CB2 receptors and does not activate cannabinoid 1 (CB1) receptors. CB1 receptors are found in the brain and are believed to be responsible for the psychological effects of cannabis.

So this suggests JWH133 may be a useful candidate for an osteoarthritis treatment. However, this is very early stage research only involving rats.

As Professor Alan Silman, medical director of Arthritis UK, says in the press coverage, this research does not support recreational cannabis use.

Where did the story come from?
The study was carried out by researchers from the University of Nottingham in the UK in collaboration with researchers from the University of Pittsburgh and Virginia Commonwealth University in the US. It was funded by Arthritis Research UK and the National Institutes of Health. 

The study was published in the peer-reviewed journal PLOS One. PLOS One is an open-access journal, meaning that all the research it publishes can be accessed for free.

This study was reported on by the Daily Express and The Telegraph. The Telegraph made no mention of the fact that the current research was in rats. This was also unclear from the over-optimistic headline in the Express. However, the report in the Express was of a higher standard, as it explained that the research was in animals and that it would take a considerable amount of time before any pill could be available for patients.

What kind of research was this?
This was a laboratory experiment on animals.

The researchers wanted to test the hypothesis that activation of cannabinoid 2 (CB2) receptors would reduce osteoarthritis pain responses in an animal model of osteoarthritis.

What did the research involve?
To create the animal model of osteoarthritis, rats had an injection of a chemical (monosodium acetate) into one of their knees (on the left rear limb). This triggered the same kind of inflammation and functional damage to the limb that occurs in humans with osteoarthritis.

The rats were then either given a drug called JWH133 or a placebo (“dummy”) injection. JWH133 binds with and activates the CB2 receptor of cells, causing them to respond. Eight rats were injected with JWH133 and eight were injected with placebo.

Pain behaviour was determined by measuring the change in weight distribution between the limbs and by testing the rats' sensitivity to pinch and touch.

Further experiments were performed on the animal model of osteoarthritis and normal rats that had been given an injection of saline (salty water) into their knee to see how JWH133 could reduce pain.

What were the basic results?
Once the rats had the injection of monosodium acetate into the knee of their left rear limb to model osteoarthritis, they placed less weight on that limb and their paw was more sensitive to pinch and touch.

Repeated injections with JWH133 significantly reduced the development of pain behaviour in the osteoarthritis model rats compared to the placebo injection.

The researchers went on to perform a series of further experiments. They found that:

treatment with JWH133 reduced the changes in inflammation-controlling chemicals which are released by osteoarthritis model rats

treatment with JWH133 reduced the firing of nerve cells in the spine in response to pain in osteoarthritis model rats, but not normal rats

osteoarthritis model rats have higher levels of the CB2 receptor “message” (mRNA) and protein in nerve cells in the spine 

The researchers then looked at the levels of CB2 receptor “message” in human spines of people who had died who had had knee osteoarthritis. They found that the more severe the disease, the lower the level of CB2 receptor “message”. The researchers say that this might reflect “events associated with later stages of joint pathology [disease]”.

How did the researchers interpret the results?
The researchers conclude that “activation of CB2 receptors attenuated [reduced] the development and maintenance of osteoarthritis-induced pain behaviour”. They go on to state that their “clinical and pre-clinical data support the further investigation of the potential of CB2 receptor agonists [chemicals that bind to the receptor and activate it] for the treatment of pain associated with osteoarthritis, in particular at earlier stages of the disease”.

This study found that a chemical called JWH133, which binds to and activates the cannabinoid 2 (CB2) receptor, could reduce osteoarthritis-induced pain behaviour in rats injected with a chemical to mimic the effects of osteoarthritis.

This early stage research supports the further investigation of the potential of chemicals which bind to activate the CB2 receptor as treatments for osteoarthritis-induced pain. However, so far the treatment has only been tested in a small number of rats injected with a chemical to mimic symptoms of osteoarthritis. This study does not show what positive or negative effect chemicals that activate the CB2 receptor may have in humans suffering from osteoarthritis.

Until further trials involving humans, such as a phase I trial are carried out, it is impossible to predict whether JWH133 will be effective, and probably more importantly, safe in humans.

If you are having problems coping with your arthritis symptoms, the NHS offers specialist services for people with chronic pain conditions. 

Read more about NHS Services for people with chronic pain.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links to the headlines
Synthetic cannabis created for osteoarthritis. The Daily Telegraph, January 7 2014
‘Synthetic cannabis’ pill could end arthritis pain for millions. Daily Express, January 7 2014
Links to the science
Burston JJ, Sagar DR, Shao P, Bai M, King E, et al. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint. PLoS ONE. Published online November 25 2013

What is Behind the Headlines?
We give you the facts without the fiction. Professor Sir Muir Gray, founder of Behind the Headlines, explains more...

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Tuesday, August 13, 2013

Behind the Headlines - Oily fish may reduce risk of rheumatoid arthritis

Behind the Headlines provides an unbiased and evidence-based analysis of health stories that make the news.  Each day the NHS Choices team selects health stories that are making headlines. These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information. Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.

Oily fish may reduce risk of rheumatoid arthritis

Eating fish could halve risk of arthritis" is the encouraging news in The Guardian, as a Swedish study found that women who regularly ate high levels of oily fish were less likely to develop rheumatoid arthritis.

Researchers asked women about their diet at two time points a decade apart to assess their intake of long-chain n-3 polyunsaturated fatty acids (omega-3 fatty acids).

The researchers then followed up the women six years after their diet was last assessed to see if they had developed rheumatoid arthritis.

They found that women whose dietary intake of omega-3 fatty acids consistently exceeded 0.21g per day at both time points had a 52% decreased risk of rheumatoid arthritis compared with women who consistently reported a dietary intake of 0.21g per day or less.

This corresponds to at least one serving of oily fish a week, or four servings a week of lean fish, such as cod.

However, the way this study was carried out means that it can't prove that eating fish directly prevented women developing rheumatoid arthritis. Despite this, there are many health benefits from regularly eating oily fish, including a reduced risk of cardiovascular disease.

Oily fish

A healthy diet should include at least two portions of fish a week, including one of oily fish such as salmon or mackerel.

However, babies, children and women who are pregnant, breastfeeding or planning to have children should have no more than two portions of oily fish a week.

The rest of us can eat up to four portions a week. This is the advised maximum level to avoid overexposure to marine pollutants. 

Read more about eating fish and shellfish and your health.

Where did the story come from?

The study was carried out by researchers from the Karolinska Institutet and Karolinska University Hospital, Sweden. It was funded by the Swedish Research Council and Committee for Research Infrastructure and the Karolinska Institutet, a medical university. 

The study was published in the peer-reviewed Annals of the Rheumatic Diseases.

This story was generally well reported by the media, but The Guardian and the Daily Express headline writers could have been a little more precise. They both talk about "arthritis", which is an umbrella term that covers a range of conditions that cause joint pain and swelling. The study in question looked at rheumatoid arthritis, which is one of the less common types of arthritis.

What kind of research was this?

Rheumatoid arthritis is an autoimmune condition where the body's own immune cells start "attacking" the joints of the body, causing pain and inflammation. The small joints of the hands and feet are most commonly first affected.

In this cohort study the researchers wanted to know if there is an association between dietary long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) and the risk of developing rheumatoid arthritis. But cohort studies cannot show causation. 

We can't conclude from the results of this study that n-3 PUFAs are directly responsible for the reduction in risk seen. This is because it is possible that there are other factors (confounders) responsible for the association seen. 

For example, it is possible that people who eat a healthier diet that includes more fatty acids also have other healthier lifestyle behaviours that may also reduce their risk of developing certain conditions, such as a healthier diet overall and taking more regular exercise.

What did the research involve?

The researchers studied 32,232 women born between 1914 and 1948 who were living in a region of Sweden.

The women completed questionnaires on height, weight, the number of children they had, educational level, smoking history, physical activity and the use of dietary supplements. 

Women who were diagnosed with non-rheumatoid arthritic conditions, had extreme energy intake, died before January 1 or took fish oil supplements were not eligible for the study.

The women completed a food frequency questionnaire at two time points: 1987 and 1997. The researchers calculated dietary intake of n-3 PUFAs by multiplying the frequency of food consumption (mainly fish and seafood) by the nutrient content of age-specific portion sizes.

New cases of rheumatoid arthritis were identified using two registers: the Swedish Rheumatology Register and the Outpatient Register of the Swedish National Board of Health and Welfare. The researchers were interested in cases that developed between January 1 2003 and December 31 2010. This was so women who had arthritis at the start of the study would not be wrongly identified as new cases.

The researchers looked at whether there was a link between the risk of developing rheumatoid arthritis and n-3 PUFAs and fish intake.

They adjusted for the following confounders:
cigarette smoking
alcohol intake
use of aspirin
energy intake

What were the basic results?

Of the 32,232 women included in the study, 205 developed rheumatoid arthritis during the period January 1 2003 to December 31 2010, an average follow-up of seven-and-a-half years.

Dietary intake of n-3 PUFAs was divided into fifths (quintiles). Women in the bottom quintiles ate 0.21g per day or less of n-3 PUFAs, according to the food frequency questionnaire in 1997. 

An intake of n-3 PUFAs of more than 0.21g per day (reported on the food frequency questionnaire in 1997) was associated with a 35% decreased risk of developing rheumatoid arthritis compared with a lower intake (adjusted relative risk [RR] 0.65; 95% confidence interval [CI] 0.48-0.90). 

The researchers calculated that 28% of rheumatoid arthritis cases could be avoided if everyone had an intake of more than 0.21g n-3 PUFAs per day.

They also found that higher dietary intakes of n-3 PUFAs further reduced the risk of rheumatoid arthritis until an intake of 0.35g per day was reached. After this level, no additional benefit was seen with a higher intake.

When women consistently reported an intake exceeding 0.21g per day (both in 1987 and 1997), this was associated with a 52% (95% CI 29-67%) decreased risk of rheumatoid arthritis compared with women who consistently reported a dietary intake of 0.21g per day or less.

The researchers also found that women who reported eating at least one serving of fish (either oily or lean) per week in both 1987 and 1997 had a 29% decreased risk of rheumatoid arthritis compared with women who ate less than one serving per week (RR 0.71, 95% CI 0.48-1.04).

How did the researchers interpret the results?

The researchers conclude that in this study, they have observed a "statistically significant inverse association between intake of dietary long-chain n-3 polyunsaturated fatty acids and rheumatoid arthritis".

They go on to suggest that "moderate consumption of fish is sufficient to reduce risk of diseases".


This is a well-designed cohort study that found an association between an increased dietary intake of long-chain n-3 polyunsaturated fatty acids and a reduced risk of rheumatoid arthritis in a cohort of middle-aged and older women in Sweden.

This study has many strengths, including:
it was prospective, meaning that information was collected as the study was being performed
it used a large sample of women taken from the general population
diet was assessed at two time points, both long before rheumatoid arthritis was diagnosed 

But because this is a cohort study, we cannot conclude from its results that dietary long-chain n-3 polyunsaturated fatty acids are directly responsible for the reduction in risk seen. This is because of the confounding factors that could also potentially be responsible for the association seen.

Although the researchers adjusted their analyses for the lifestyle factors of smoking and alcohol intake, which are associated with the risk of rheumatoid arthritis, it is possible that people who eat a healthier diet that includes more fatty acids could also have other healthy lifestyle behaviours. This could include having a healthier diet overall (such as a diet with plenty of fruit and vegetables and low in saturated fats) and taking more regular exercise.

In addition, this study provides no information about whether dietary intake of long-chain n-3 polyunsaturated fatty acids is associated with a reduced risk of rheumatoid arthritis in men or younger women. Further studies are required to confirm whether long-chain n-3 polyunsaturated fatty acids really do reduce your risk of developing rheumatoid arthritis. 

However, it is currently recommended that people should aim to eat at least two portions of fish a week, including one portion of oily fish. Babies, children and women who are pregnant, breastfeeding or planning to have children should have no more than two portions of oily fish a week.

Eating this amount of fish would provide more than 0.21g of long-chain n-3 polyunsaturated fatty acids, which was the level associated with a reduction in the risk of developing rheumatoid arthritis.

Read more about eating fish and shellfish and your health.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links to the headlines

Eating fish could halve risk of arthritis. The Guardian, August 12 2013

Eating oily fish 'halves rheumatoid arthritis risk'. BBC News, August 13 2013

Eating salmon once a week 'cuts rheumatoid arthritis risk in half'. Daily Mirror, August 13 2013

Eating salmon once a week 'reduces risk of rheumatoid arthritis by half'. Mail Online, August 13 2013

How oily fish can halve risk of arthritis. Daily Express, August 13 2013
Links to the science

Di Giuseppe D, Wallin A, Bottai M, et al. Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: a prospective cohort study of women. Annals of the Rheumatic Diseases. Published online August 12 2013

Saturday, November 3, 2012

Hepatitis C virus infection and autoimmune diseases

Hepatitis C virus infection and autoimmune diseases

Authors: Paroli M, Iannucci G, Accapezzato D
Published Date October 2012 Volume 2012:5 Pages 903 - 907

Marino Paroli,1 Gino Iannucci,2 Daniele Accapezzato2
1Department of Biotechnology and Medical-Surgical Sciences, 2Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy

Hepatitis C virus (HCV) infection is associated with a number of extrahepatic disorders. The most studied conditions associated with HCV are type II mixed cryoglobulinemia and B cell lymphoma. However, many reports suggest that HCV might also be associated with a number of autoimmune disorders, both organ-specific and not organ-specific. Although concomitant treatment of HCV infection is a confounding factor when ascertaining the actual role of HCV in inducing autoimmune disease, a considerable amount of experimental data indicates that HCV is able to subvert the immune system and consequently induce autoimmunity. In the present review, we report a series of observations which associate chronic HCV infection with the onset of autoimmune disorders.

Keywords: hepatitis C virus, immune regulation, autoimmune diseases

In 1987, hepatitis C virus (HCV) was discovered to be the causative agent of a type of hepatitis previously known as non-A, non-B hepatitis.

1 However, it has been observed with time that presence of the virus might be also responsible for extrahepatic manifestations.2 Therefore, the concept of systemic HCV infection has emerged.3,4 The most studied HCV-related conditions are lymphoproliferative disorders, including type II mixed cryoglobulinemia,5–7 which can evolve into frank lymphoma,8,9 and lymphomas unrelated to mixed cryoglobulinemia.10–12 Among the hematologic disorders, monoclonal gammopathies associated with HCV infection have also been described.13

This review focuses on non-lymphoproliferative disorders as a manifestation of chronic HCV infection, namely autoimmune diseases. HCV can in fact subvert the immune system in several ways, from expanding selective B cell subsets to induce breaking tolerance and by reaction of T cells against apoptosis-derived self-antigens, with consequent promotion of T helper-17 cells.14–18

The possible mechanisms by which autoimmunity can be triggered by HCV infection are shown in Figure 1. However, the causal relationship between HCV infection and the onset of clinically relevant autoimmunity is still a matter of debate. This review may help the clinician to understand whether the onset of autoimmune manifestation in the course of HCV might actually be related to the presence of the virus.

Figure 1
Possible mechanisms of autoimmunity induced by hepatitis C virus (HCV).

HCVinfects hepatocytes and interacts with B lymphocytes. HCVand hepatocyte-derived apoptotic proteins are taken up by tissue-resident dendritic cells, which mature and migrate into the draining lymph nodes. Here they activate naïve HCV-specific and self-peptide-specific T cells. These cells in turn differentiate into effector proinflammatory T helper-1, T helper-17, or cytotoxic T lymphocytes. Effector T cells can recognize either HCV-derived peptides on the hepatocyte surface or peptides self-expressed by noninfected cells, with the possible triggering of autoimmunity. Specific B cells are activated by T helper cells via CD40L/CD40 interaction and are induced to produce both anti-HCV and natural nonorgan-specific autoantibodies. These autoantibodies can react against components of self. Finally, HCV-specific T and B cells can recognize self-antigens by a mechanism of molecular mimicry between virus and host.

Abbreviation: MHC, major histocompatibility complex.

Thyroid disorders
In the course of HCV infection, both hypothyroidism and hyperthyroidism may emerge. Hashimoto’s thyroiditis is the most common thyroid disorder observed in patients with HCV infection. Treatment with interferon-alpha (IFNA) can be an additional risk factor for the development of thyroid complications. In fact, IFNA can induce autoimmunity by several molecular mechanisms, including polymorphisms in the IFNA-signaling pathways, a feed-forward loop of IFNA production, and a mutually positive regulatory feedback loop between IFNA and estrogen receptor-α. Increased levels of IFNA have numerous immunomodulatory functions, including activating both innate and adaptive immune responses.

19 In a recent study, 293 patients with chronic HCV who underwent IFNA therapy for 24 or 48 weeks, were investigated for thyroid function.20 The investigators found that hypothyroidism was the most frequent thyroid disease, especially during the first cycle of IFNA. Genotype 1 virus was associated with a twofold risk of developing the illness. However, approximately 34% of thyroid disease was transient.

In a retrospective study of 288 patients who received IFNA-ribavirin for HCV over a 2-year period, thyroid function was assessed during a 24- or 48-week course of therapy.

21 The authors concluded that although thyroid disease was common in this cohort, just 2.3% patients required ongoing therapy. Interestingly, pre-IFNA-ribavirin serum thyroid-stimulating hormone and thyroid peroxidase antibody titers were found to predict development of thyroid disease in this group of patients. This finding highlights the fact that IFNA-associated thyroiditis during treatment of HCV infection is critically influenced by individual factors. In another report, a case of fluctuating and wavering thyrotropin autoantibodies of both a stimulating and blocking nature was described.22 The autoantibody profile was clearly modified during IFNA therapy and settled into a new equilibrium on completion of treatment. This case highlights the possible existence of a dual thyroid autoantibody population associated with HCV, and its possible modulation by IFNA therapy. There has also been a report of a 69-year-old Japanese man who developed Graves’ ophthalmopathy while receiving IFNA-ribavirin.23

However, several other studies have shown that the prevalence of thyroid disease is increased regardless in patients infected with HCV compared with normal subjects, after exclusion of patients being treated with IFNA.24–26

In this regard, genetic and environmental factors seem to play an important role,27–29 and subclinical hypothyroidism is observed in a significant proportion of patients with chronic HCV infection.30,31 To explain the relationship between HCV infection and thyroid disease, it has been hypothesized recently that HCV envelope proteins can induce thyroidal inflammation directly, thereby triggering thyroiditis via a so-called "bystander activation" mechanism.

In a recent study,32 significant levels of CD81 mRNA as well as CD81 protein (one of the putative HCV cell receptors 33) were found on thyroid cells. Incubation of thyroid cells with HCV envelope glycoprotein E2 resulted in binding of E2 to thyroid cells, with activation of interleukin-8, an important proinflammatory cytokine. Intriguingly, thyroid cells incubated with E2 continued to proliferate normally and did not undergo apoptosis, as was reported in hepatocytes.

The authors of this study concluded that HCV envelope glycoprotein E2 can bind to CD81 receptors expressed on thyroid cells and induce a cascade of signals, with possible onset of thyroiditis in genetically susceptible individuals. In conclusion, it is advisable for the clinician to monitor thyroid function regularly in the course of chronic HCV, and in particular during treatment with IFNA-based regimens.

Rheumatoid arthritis

Polyarthritis can be observed in the course of HCV infection, and in some cases is associated with mixed cryoglobulinemia.34,35 A recent study investigated 45 HCV-infected patients and 30 patients with rheumatoid arthritis fulfilling American College of Rheumatology classification criteria for rheumatoid arthritis but negative for HCV.36 The study focused on the significance of anti-mutated citrullinated vimentin (MCV) antibodies, which were recently suggested for inclusion in the diagnostic workup for rheumatoid arthritis. Anti-MCV antibodies, anti-cyclic citrullinated peptide (CCP) antibodies, rheumatoid factor, and cryoglobulins were measured. The most frequent pattern was symmetric polyarthralgia, and the joints most frequently involved were the wrists, metacarpophalangeal joints, shoulders, and knees. In HCV arthropathy, anti-MCV was positive in 30% of cases, anti-CCP in 0%, and rheumatoid factor in 73.3%, whereas in rheumatoid arthritis, anti-MCV was positive in 93.3%, anti-CCP in 96.7%, and rheumatoid factor in 86.7% of cases. Therefore, the authors concluded that anti-CCP still plays a major role in differentiating between rheumatoid arthritis and HCV arthropathy.

Another recent study assessed the diagnostic utility of anti-CCP antibodies in comparison with rheumatoid factor in distinguishing between rheumatoid arthritis and HCV-related polyarthropathy.
37 Serum anti-CCP antibodies and rheumatoid factor were measured in 30 patients with rheumatoid arthritis and 22 patients with HCV-related polyarthropathy. Anti-CCP antibodies were positive in 83.3% of patients with rheumatoid arthritis and in 4.5% in patients with HCV and polyarthropathy. Rheumatoid factor was positive in 90% of patients with rheumatoid arthritis and in 81.1% of HCV patients with polyarthropathy. Anti-CCP antibodies showed higher specificity than rheumatoid factor for rheumatoid arthritis (95.4% versus 18.2%). However, the sensitivity of anti-CCP was comparable with that of rheumatoid factor (83.3% versus 90%).

The conclusion of this study is again that anti-CCP antibodies are the most reliable laboratory markers for differentiating between rheumatoid arthritis and HCV-related polyarthropathy. Therefore, there is consolidated evidence indicating that "true" rheumatoid arthritis is uncommon in HCV patients, and that the arthritis observed is, in most cases, a nonerosive intermittent oligoarticular arthritis.

Sjögren’s syndrome

Sjögren’s syndrome is an autoimmune disease characterized by involvement of exocrine glands showing significant T cell infiltration. The inflammatory process involves mainly the salivary and lacrimal glands, leading to both xerostomia and xerophthalmia. Sjögren’s syndrome is also characterized by nonerosive arthritis, which may be accompanied by systemic symptoms, including asthenia. Laboratory investigation shows positivity for SSA and/or SSB autoantibodies, often associated with the presence of rheumatoid factor. Sjögren’s syndrome can present as a primary disease or secondary to rheumatoid arthritis or systemic lupus erythematosus.

38 Definitive evidence that HCV infection may trigger Sjögren’s syndrome is still lacking. A correlation between Sjögren’s syndrome and mixed cryoglobulinemia has been repeatedly reported.39,40 However, different studies have been carried out subsequently to ascertain the possible relationship between HCV infection and Sjögren’s syndrome.41,42 In an interesting study, the clinical and immunologic characteristics of 35 patients with chronic HCV infection and a well documented diagnosis of Sjögren’s syndrome were reported.43 Compared with 60 patients with primary Sjögren’s syndrome who tested negative for HCV antibodies, patients with Sjögren’s syndrome and HCV showed a higher mean age, a lower prevalence of parotidomegaly, and a higher prevalence of liver involvement. Moreover, the patients with HCV-related Sjögren’s syndrome showed a higher prevalence of anti-gastric parietal cell antibodies, anti-mitochondrial antibodies, cryoglobulinemia, hypocomplementemia, and a lower prevalence of SSA autoantibodies.44 Therefore, the immunologic characteristics of HCV infection and Sjögren’s syndrome appear to be different, although common mechanisms linking HCV-associated Sjögren’s syndrome and lymphoproliferative disorders have been hypothesized.45 Further studies are needed to clarify the role of HCV infection in Sjögren’s syndrome.

Anecdotal observations

Many other autoimmune conditions have been related to HCV infection. Glomerulonephritis has been associated with HCV, especially in children, 46,47 and immune-mediated skin diseases, especially oral lichen planus, have been linked with HCV.48–50 Neurologic autoimmune diseases, including myelitis51 and encephalomyelitis,52 as well as several neuromuscular diseases, have also been reported in the course of HCV infection.53 A case of relapsing polychondritis associated with HCV infection has been recently observed.54 Finally, autoimmune mechanisms have been implicated in thrombocytopenia associated with chronic HCV.55–57


HCV infection not only affects the liver, but is also associated with extrahepatic disorders, including autoimmune disorders. There is experimental evidence showing that HCV can subvert the immune system, possibly leading to the onset of autoimmunity. However, IFNA, used in the treatment of HCV infection, is a powerful inducer of autoimmunity, and it is sometimes difficult to discriminate between the effect of HCV and IFNA in inducing an autoimmune reaction. On the other hand, IFNA has been found to improve some HCV-related autoimmune diseases, suggesting that these might be mediated by inhibition of HCV replication or viral clearance. Therefore, IFNA can be considered on the one hand as a trigger for autoimmunity in patients with HCV but, on the other hand, as a therapeutic tool in some cases of autoimmune disease. In light of all these considerations, further study is needed to clarify the actual role of HCV infection in the induction of clinically significant autoimmunity, and to identify additional autoimmune disorders in which concomitant presence of HCV might possibly be involved in the pathogenesis.

The authors report no conflicts of interest in this work.



Wednesday, October 10, 2012

Etanercept Recommended for RA Complicated by Hepatitis C

By: M. ALEXANDER OTTO, Family Practice News Digital Network

NEWPORT BEACH, CALIF. – Etanercept and a few other tumor necrosis factor inhibitors should be considered first-line therapy for treating rheumatoid arthritis in patients with active hepatitis C virus infection, according to Dr. Leonard Calabrese, chair of clinical immunology and professor of medicine at the Cleveland Clinic.
A systematic literature review (Rheumatology (Oxford) 2011;50:1700-11) that included 153 patients – 91 with rheumatoid arthritis (RA) – "demonstrated quite clearly that there are no safety signals from this. TNF inhibitors work in the same general manner with the same predicted responses in hepatitis C patients as they do in patients who are uninfected," he said.
"Most of the data are on etanercept," and recent guidelines from the American College of Rheumatology recommend it in RA patients with hepatitis C based on observations and other level-C evidence, he noted.
For those and other reasons, "I consider TNF inhibitors first-lines of therapy. These drugs can [also] be used concomitantly" with hepatitis C treatments, including protease inhibitors, which seem to greatly improve cure rates when included with other antiviral therapies, he said at Perspectives in Rheumatic Diseases 2012, sponsored by Skin Disease Education Foundation (SDEF).
"When we find somebody with hepatitis C in our practice, we are doing them a huge favor because we can bring them into the circle of care and treat the thing that is more serious than their" RA, Dr. Calabrese said.

Meanwhile, the guidelines do not recommend methotrexate or leflunomide in the setting of hepatitis C virus infection because the drugs might cause additional liver damage.
Among others, Dr. Calabrese screens baby boomers – the largest reservoir of hepatitis C in the United States – and people going on to high-risk drugs, "which is basically anyone going onto a" disease-modifying antirheumatic drug, he said.
"Having antibody to hepatitis C does not prove you have chronic hepatitis C infection, only that you have immunologic memory to the virus. The confirmatory test [for active infection] is the presence of [hepatitis C virus] RNA in the serum, detected by" polymerase chain reaction. "When you find this, the most important part is to refer [the patient] to a hepatologist," he said.
Screening for hepatitis C based on liver enzymes "is a fallacy," he said. Patients with chronic infection can have normal levels, and persistently normal levels do not rule out significant disease.

Perhaps 5 million people in the United States have active, chronic infection. There’s been a slight uptick in cases among men who have sex with men and drug users in rural areas who inject prescription drugs, he noted.

Dr. Calabrese is a consultant for Aventis, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer. He is a speaker for Amgen. SDEF and this news organization are owned by Frontline Medical Communications.

Thursday, September 29, 2011

Consider Hepatitis C Infection in Some Arthritis Patients

CHICAGO – Sept 29

Data from two new trials, one in press and the other ongoing, suggest that two established tumor necrosis factor inhibitors may be the safest drugs for treatment of rheumatoid arthritis in a patient with active hepatitis C virus infection.

The recent pilot study (Journal of Hepatology, in press) of 50 patients with coexisting rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection clearly demonstrated that adding etanercept to traditional antiviral therapy was associated with clearing HCV and normalizing liver enzymes, Dr. Leonard H. Calabrese said at the Midwest Rheumatology Summit.

"This was kind of an opening salvo to us, saying, this is our drug. We should be looking at this ... to see if it’s an option to use to treat autoinflammatory disease and, in particular, rheumatoid arthritis," said Dr. Calabrese.

The ongoing Partner Trial is designed to answer the question of whether a tumor necrosis factor (TNF) inhibitor enhances antiviral responses to traditional therapy, specifically the efficacy of infliximab as an adjunct to peginterferon alfa-2b and ribavirin in the treatment of HCV genotype 1.

"One thing that is not a good idea is to use hepatotoxic drugs (like) methotrexate," said Dr. Calabrese.

Treatment is not the only challenge in caring for the patient with overlapping RA and HCV; just making the HCV diagnosis can be difficult.

"The most undiagnosed infection in our country is hepatitis C. There are probably about 3 million people walking around who are infected, who don't know it," said Dr. Calabrese, professor of medicine at the Cleveland Clinic’s Lerner College of Medicine at Case Western Reserve University. Most patients with undiagnosed hepatitis C have chronic infection, which is relatively asymptomatic, he said. "That’s why screening programs are essential."

He described a 49-year-old woman with a history of polyarthritis who presented for evaluation after a 7-month history of migratory arthritis involving feet, hands, wrists, and knees. The patient had a "fairly normal" hemogram and normal alanine transaminase (ALT) and was positive for the anti–cyclic citrullinated peptide (CCP) antibody.

"The most undiagnosed infection in our country is hepatitis C."

"So she clearly has rheumatoid arthritis ... and is an excellent candidate for methotrexate," he said. Lab results showed the woman to be positive for the HCV antibody, and negative for hepatitis B surface antigen and hepatitis B core antibody.

"So the question is, does this patient have active hepatitis C infection?" said Dr. Calabrese. And if so, how would that influence treatment decisions?

Nearly half of patients with chronic HCV have ALTs within the normal range, so the test has no negative predictive value. "The gold standard of diagnosis in HCV is the presence of fibrosis on liver biopsy," said Dr. Calabrese. "The reality is that if you have people with persistently normal ALT levels, upon biopsy, 75% have some evidence of damage, and about a third of them have advanced fibrosis."

This patient was found to have a normal ALT-38 u/mL, to have 1.2 million copies/mL of HCV-RNA, and to have genotype 1. Her liver appeared normal on ultrasound.

This patient has normal ALT but clearly has HCV, he said. "Normal liver enzymes do nothing at this juncture to tell us that this patient does not have a significant problem." While a biopsy is invasive, it has a very acceptable rate of complications, he said.

The alternative to biopsy is the transient elastography test, widely used in Europe. It is noninvasive and accurate, but not yet approved in the United States.

And the 49-year-old woman? "Patients such as this I would treat with a TNF-inhibitor monotherapy, and if that patient needs treatment, or my hepatologist says ‘I want to start this patient on therapy for hepatitis C next month’? Let’s do it – and keep them right on their TNF-inhibitor. We have enough data now to know that it’s probably a safe thing," he said.

Dr. Calabrese disclosed consultant and/or speaking income from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Pfizer, and Roche. The Midwest Rheumatology Summit acknowledged educational grants from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB.


Wednesday, March 16, 2011

The Approach to the Painful Joint

The Approach to the Painful Joint

Author: Alan Baer, MD, Associate Professor of Medicine, Department of Medicine, Johns Hopkins University; Clinical Director, Johns Hopkins Rheumatology Practice at Good Samaritan Hospital; Chief of Rheumatology, Good Samaritan HospitalCoauthor(s): Vinod Patel, MD, Medical Director, Jefferson Family Medicine Center; Clinical Assistant Professor, Department of Family Medicine, State University of New York at Buffalo; Robert McCormack, MD, Associate Professor of Clinical Emergency Medicine, University at Buffalo School of Medicine and Biomedical Sciences

Contributor Information and Disclosures



Joint pain can be caused by diverse processes, including inflammation, cartilage degeneration, crystal deposition, infection, and trauma. The differential diagnoses of joint pain are generated in large part from the history and physical examination.1 Screening laboratory test results serve primarily to confirm clinical impressions and can be misleading if used indiscriminately. The initial aim of the evaluation is to localize the source of the joint symptoms and to determine the type of pathophysiologic process responsible for their presence.


Joint pain may arise from structures within or adjacent to the joint or may be referred from more distant sites. Sources of pain within the joint include the joint capsule, periosteum, ligaments, subchondral bone, and synovium, but not the articular cartilage, which lacks nerve endings. Determination of the anatomic part responsible for joint pain is often a difficult yet critical task, since it guides the approach to diagnosis and therapy. Knowledge of the anatomy of complex joints, such as the knee, shoulder, and ankle, aids in this assessment.

The evaluation of joint pain, both in terms of the history and the physical examination findings, is best achieved through an understanding of the basic pathophysiologic types of joint disease. These include synovitis, enthesopathy, crystal deposition, infection, and structural or mechanical derangements. These types of joint disease are not mutually exclusive. Examples of pathologic processes that commonly coexist include crystal deposition in osteoarthritis, synovitis in enthesopathies, and cartilage destruction in chronic synovitis.


The synovial membrane is the principal site of inflammation in persons with rheumatoid arthritis (RA) and many other inflammatory arthritides.2 Synovitis is characterized pathologically by neovascularization; infiltration of the synovium with lymphocytes, plasma cells, and macrophages; and synovial lining cell hyperplasia. These cause synovial proliferation, recognized clinically by warmth, tenderness, and a boggy consistency of the soft tissues overlying the involved joint. The inflamed synovium may infiltrate and erode intra-articular bone and cartilage.


The enthesis is the transitional zone where collagenous structures such as tendons and ligaments are interwoven into bone.3 Other examples of entheses include the interface between cortical bone and the periosteum and between vertebral bodies and the annulus fibrosus. It is the principal site of pathology in the seronegative spondyloarthropathies. As a result of inflammation at these interfaces, the radially oriented collagen fibers undergo metaplasia, forming fibrous bone. These metaplastic transformations result in new bone formation (periostitis), gradual ossification of syndesmoses (eg, the sacroiliac joints), and syndesmophyte formation along the outer fibers of the vertebral discs. When enthesitis occurs in a diarthrodial joint, a secondary synovitis may develop.

Crystal deposition

The deposition of crystals in articular structures may lead to symptomatic joint disease. The responsible crystals include monosodium urate, calcium pyrophosphate dihydrate, basic calcium phosphate (including hydroxyapatite), and calcium oxalate.

Monosodium urate crystal deposition occurs on the surface of hyaline cartilage, within the synovium and in periarticular structures, including tendon sheaths and bursae. As a result, inflammation related to urate crystal deposits may be localized to a bursa or tendon sheath adjacent to the joint or may be widespread, involving multiple joint structures. Clinically, an acute gouty joint is inflamed, with overlying erythema, warmth, or both.4 Prominent periarticular inflammation may resemble cellulitis.

Calcium pyrophosphate crystal deposition is confined to hyaline cartilage, fibrocartilage, and areas of chondroid metaplasia (ie, degenerated areas of tendons, ligaments, and joint capsule) within the joint.5 Shedding of these crystals into the joint space may trigger an acute inflammatory arthritis, known as pseudogout.

Infectious arthritis

The synovium may become the seat of acute or chronic infections related to bacterial, fungal, or viral organisms.6 These infections almost always arise from blood-borne organisms and may be part of a systemic infection. The infection is based in the synovium. The cardinal pathologic findings include intense infiltration by neutrophils with resultant necrosis of the synovium and subsequent formation of granulation and scar tissue. A dense mass of fibrin, infiltrated by neutrophils, forms over the surface of the synovium. Bacterial products released within the joint are capable of producing rapid cartilage destruction.

Structural or mechanical joint derangement

Degeneration of the articular cartilage is the principal pathologic feature of osteoarthritis.7 It occurs in response to both local and host factors. Local factors include previous joint trauma (eg, meniscal tears), congenital or developmental joint alterations (eg, congenital hip dysplasia, slipped capital femoral epiphysis), alterations of the subchondral bone (eg, osteopetrosis, avascular necrosis, Paget disease), alterations of supporting structures (eg, hypermobility), and cartilage derangements (eg, ochronosis, crystal deposition). Host factors include genetic traits, obesity, and occupation. Damage to the articular cartilage is associated with subchondral bone sclerosis and marginal osteophyte formation. Patients with osteoarthritis may have an associated synovitis, with the formation of bland synovial effusions.



Two determinations serve to focus the history and physical examination of a patient with joint pain.1

The first determination is whether the pain stems from the joint or an adjacent bursa, tendon, ligament, bone, or muscle or whether it is referred from a visceral organ or nerve root. This is generally more difficult with pain in proximal, larger joints. Thus, hip pain can arise from degenerative disc disease or stenosis of the lumbar spine8 , aortoiliac occlusive disease, hip arthritis, or trochanteric bursitis.

If the pain is stemming from the joint, three broad categories of joint disease must be differentiated.9

The first category is inflammatory arthritis.10 It is characterized by inflammation affecting joint structures, such as the synovium, synovial cavity, and entheses. The second category is noninflammatory arthritis.7 This is joint disease resulting primarily from alterations in the structure or mechanics of the joint. The joint disease may occur as a result of (1) cartilage or meniscal damage with or without concomitant alterations in the structure of the subchondral bone or (2) alterations in joint anatomy as a result of congenital, developmental, metabolic, or past inflammatory diseases. The third category is arthralgia.11 Apart from joint tenderness, abnormalities of the joint cannot be identified. Such patients may have a syndrome of altered pain sensation (eg, fibromyalgia) or an early rheumatic syndrome whose clinical signs are not yet apparent or too subtle for detection (eg, arthralgias of systemic lupus erythematosus [SLE]).

These types of joint disorders may occur together in the same joint. Inflammatory joint disorders often lead to structural derangement of the joint, and, similarly, structural joint problems (eg, traumatic arthritis, osteoarthritis) often have an associated, albeit minor, inflammatory component. Finally, reports of joint pain and tenderness in any type of joint disease are influenced by the patient's emotional state and pain threshold.

  • Symptoms of joint disease
    • Pain
      • With inflammatory joint disease, the pain is present both at rest and with motion. It is worse at the beginning than at the end of usage.
      • With noninflammatory (ie, degenerative, traumatic, or mechanical) joint disease, the pain occurs mainly or only during motion and improves quickly with rest. Patients with advanced degenerative disease of the hips, spine, or knees may also have pain at rest and at night.
      • Pain that arises from small peripheral joints tends to be more accurately localized than pain arising from larger proximal joints. For example, pain arising from the hip joint may be felt in the groin or buttocks, in the anterior portion of the thigh, or in the knee.
    • Stiffness
      • Stiffness is a perceived sensation of tightness when attempting to move joints after a period of inactivity. It typically subsides over time. Its duration may serve to distinguish inflammatory from noninflammatory forms of joint disease.
      • With inflammatory arthritis, the stiffness is present upon waking and typically lasts 30-60 minutes or longer.
      • With noninflammatory arthritis, stiffness is experienced briefly (eg, 15 min) upon waking in the morning or following periods of inactivity.
    • Swelling
      • With inflammatory arthritis, joint swelling is related to synovial hypertrophy, synovial effusion, and/or inflammation of periarticular structures. The degree of swelling often varies over time.
      • With noninflammatory arthritis, the formation of osteophytes leads to bony swelling. Patients may report gnarled fingers or knobby knees. Mild degrees of soft tissue swelling do occur and are related to synovial cysts, thickening, or effusions.
    • Limitation of motion
      • Loss of joint motion may be due to structural damage, inflammation, or contracture of surrounding soft tissues.
      • Patients may report restrictions on their activities of daily living, such as fastening a bra, cutting toenails, climbing stairs, or combing hair.
    • Weakness
      • Muscle strength is often diminished around an arthritic joint as a result of disuse atrophy.
      • Weakness with pain suggests a musculoskeletal cause (eg, arthritis, tendonitis) rather than a pure myopathic or neurogenic cause.
      • Manifestations include decreased grip strength, difficulty rising from a chair or climbing stairs, and the sensation that a leg is "giving way."
    • Fatigue
      • Fatigue is usually synonymous with exhaustion and depletion of energy in patients with arthritis.
      • With inflammatory polyarthritis, the fatigue is usually noted in the afternoon or early evening.
      • With psychogenic disorders, the fatigue is often noted upon arising in the morning and is related to anxiety, muscle tension, and poor sleep.
  • Historical features important to the differential diagnoses
    • Temporal pattern of arthritis
      • The onset of symptoms can be abrupt or insidious. With an abrupt onset, joint symptoms develop over minutes to hours. This may occur in the setting of trauma, crystalline synovitis, or infection. With an insidious pattern, joint symptoms develop over weeks to months. This onset is typical of most forms of arthritis, including rheumatoid arthritis (RA) and osteoarthritis.
      • Duration of symptoms is considered either acute or chronic. Acute is less than 6 weeks in duration; chronic is 6 or more weeks in duration.
      • The temporal patterns of joint involvement are migratory, additive or simultaneous, and intermittent. With a migratory pattern, inflammation persists for only a few days in each joint (eg, acute rheumatic fever, disseminated gonococcal infection). With an additive or simultaneous pattern, inflammation persists in involved joints as new ones become affected. With an intermittent pattern, episodic involvement occurs, with intervening periods free of joint symptoms (eg, gout, pseudogout, Lyme arthritis).
    • Number of involved joints
      • Monoarthritis is the involvement of one joint.
      • Oligoarthritis is the involvement of 2-4 joints.
      • Polyarthritis is the involvement of 5 or more joints.
    • Symmetry of joint involvement
      • Symmetric arthritis is characterized by involvement of the same joints on each side of the body. This symmetry is typical of RA and SLE.
      • Asymmetric arthritis is characteristic of psoriatic arthritis, reactive arthritis (Reiter syndrome), and Lyme arthritis.
    • Distribution of affected joints
      • The distal interphalangeal joints of the fingers are usually involved in psoriatic arthritis, gout, or osteoarthritis but are usually spared in RA.
      • Joints of the lumbar spine are typically involved in ankylosing spondylitis but are spared in RA.
    • Distinctive types of musculoskeletal involvement
      • Spondyloarthropathy involves entheses, leading to heel pain (inflammation at the insertions of the Achilles tendon and/or plantar fascia), dactylitis (sausage digits), tendonitis, and back pain (sacroiliitis and vertebral disc insertions).
      • Gout commonly involves tendon sheaths and bursae, resulting in superficial inflammation.
    • Extra-articular manifestations
      • Constitutional symptoms suggest an underlying systemic disorder and are not expected in patients with degenerative joint disease. These may include fatigue, malaise, and weight loss.
      • Skin lesions may be present. Physical examination of the skin, but not the joints, may indicate the specific diagnosis of a number of rheumatic diseases. Examples include SLE, dermatomyositis, scleroderma, Lyme disease, psoriasis, Henoch-Schönlein purpura, and erythema nodosum.
      • Ocular symptoms or signs are also possible. Episcleritis and scleritis may be associated with RA or Wegener granulomatosis, anterior uveitis with ankylosing spondylitis, and iridocyclitis with juvenile RA. Conjunctivitis may be caused by reactive arthritis.


The musculoskeletal examination helps distinguish joint inflammation (eg, RA) from joint damage (eg, degenerative joint disease). It can also help elucidate the site of musculoskeletal involvement (eg, synovitis, enthesitis, tenosynovitis, bursitis) and the distribution of joint involvement.

  • Signs of inflammatory joint disease
    • Synovial hypertrophy
      • This is the most reliable sign of an inflammatory arthritis.
      • The synovial membrane is normally too thin to palpate. In a person with chronic inflammatory arthritis, the synovial membrane has a doughy or boggy consistency, a feature best appreciated at the joint line or margin.
    • Joint effusions
      • Effusions develop in response to synovial inflammation, trauma, anasarca, intra-articular hemorrhage (hemarthrosis), or an adjacent focus of acute inflammation (sympathetic effusion).
      • These are detected by performing fluid ballottement or cross-fluctuation through the synovial cavity.
    • Pain with motion, particularly at the extremes of joint motion
      • Pain throughout the whole range of motion is observed in a person with an acutely inflamed joint.
      • Pain experienced as the joint is gently forced (ie, stressed) towards its limitation of range is suggestive of synovitis.
      • Pain not present throughout the entire range of motion may indicate an extra-articular source, such as tendinitis.
    • Erythema and warmth
      • Erythema of the joint is restricted to acute inflammatory forms of arthritis, such as gout, septic arthritis, or acute rheumatic fever. It is rare in persons with RA but may occasionally occur in those with psoriatic arthritis.
      • Warmth of the joint is a sensitive sign of inflammatory arthritis and can be detected by passing the hand back and forth from the joint to a neutral area distal or proximal. Differences in warmth can also be detected by comparing the same joint on each side of the body.
    • Limited range of motion: In a person with inflammatory joint disease, limitation of motion results from the presence of a tense effusion, markedly thickened synovium, adhesions, capsular fibrosis, or pain.
    • Joint tenderness
      • This is a sensitive sign of joint disease, but it is not specific for inflammatory arthritides.
      • In an acutely inflamed joint, tenderness can be elicited over the entire synovial reflection.
      • Focal tenderness may indicate a focus of inflammation outside the joint, such as tendinitis, osteomyelitis, or fracture.
      • The presence of joint tenderness in the absence of other joint abnormalities must be interpreted in the context of the patient's emotional state.
  • Signs of degenerative or mechanical joint disease
    • Bony overgrowth of the joints (osteophytes): Those located at the distal interphalangeal joints are called Heberden nodes, while those located at the proximal interphalangeal joints are called Bouchard nodes.
    • Limited range of motion: In persons with degenerative/traumatic joint disease, the limitation of motion results from intra-articular loose bodies, osteophyte formation, or subluxation.
    • Crepitus during active or passive range of motion
      • A palpable or audible grating sensation is produced during motion of the joint.
      • Soft, fine crepitus may be felt (or heard with a stethoscope) in a rheumatoid joint when the cartilage surface is no longer smooth.
      • Coarse crepitus or grating may be felt in joints severely damaged by long-standing rheumatoid or degenerative arthritis.
    • Joint deformity: Several types must be distinguished.
      • Restriction in the normal range of motion, such as a lack of full joint extension that results in a flexion deformity, is one type.
      • Another is malalignment of the articulating bones, such as ulnar deviation of the fingers or valgus deformity of the knee.
      • The third type is an alteration in the relationship of the two articulating surfaces, such as subluxation (ie, some contact between the two articulating surfaces) and dislocation (ie, complete loss of contact between the two articulating surfaces).
  • Techniques of the musculoskeletal examination
    • Inspection
      • Each joint has a characteristic or normal appearance, and each assumes a characteristic resting position.
      • Compare one side of the body with the other in order to detect joint abnormalities, including swelling, deformity, overlying erythema, or wasting of the periarticular musculature.
      • With a sagittal view of the patient, take note of joint deformities that result from the lack of full extension of a joint (eg, flexion deformities).
      • With a coronal view of the patient, take note of joint malalignment, which may result in valgus or varus deformities.
    • Palpation
      • Palpation of the joints is used to assess for signs of inflammation (eg, warmth, synovial hypertrophy, joint effusion, tenderness) and for signs of joint damage (eg, bony swelling, crepitus).
      • The examiner should palpate with enough pressure to blanch his or her thumbnail. This ensures that the assessment of joint tenderness is uniform. The application of this amount of force during palpation should not cause pain in a normal joint.
    • Assessment of range of motion
      • Assess limitation of passive motion by comparing it with the expected range of motion observed in healthy individuals and with the range of motion in the contralateral joint.
      • Active range of motion can be used to assess the presence of pathology in juxta-articular structures, such as tendons and bursae.
      • Pain occurring during only a portion of the range of motion may be related to an extra-articular structure, such as a tendon or bursa.
      • Assess pain with joint motion; observe the patient's face for wincing.
      • Assess crepitus by palpating the joint with one hand while moving the joint passively with the other. In the lower extremities, crepitus of the hip or knee can sometimes be heard as the patient arises from a chair, climbs a step, or pivots on the affected joint.
      • Assess instability or abnormal mobility by applying forces to the relaxed joint in planes of motion normally associated with little or no motion. Instability of a lower extremity joint (eg, knee, ankle) should also be assessed by observing the joint during weight-bearing and walking. Instability of the joint may be due to laxity of ligaments or destruction of the articular surface.
  • Examination techniques useful for detection of arthritis in specific joints
    • Hands
      • To detect synovial effusions in interphalangeal joints, gently squeeze the superolateral joint lines with the thumb and index finger while palpating the volar and dorsal sides with the opposite thumb and finger. Use the fingers to detect a ballooning effect as pressure is applied to the joint.
      • To detect metacarpophalangeal (MCP) joint synovitis, gently squeeze the dorsal aspects of the fully extended MCP joint distally with the thumb and index finger of one hand while screening for a ballooning effect with the same fingers of the opposite hand placed over the proximal aspects of the joint.
      • To assess grip strength, the patient is asked to squeeze two adjacent fingers of the examiner with maximum force.
    • Wrists
      • For wrist assessment, support the wrist in 15° flexion. Palpate the dorsal aspect of the radiocarpal and ulnocarpal joints for a spongy consistency, which is indicative of synovial hypertrophy.
      • Percuss over the volar aspect of the wrist; elicitation of paresthesias in the median nerve distribution is indicative of carpal tunnel syndrome.
    • Elbows
      • Assess for flexion deformity (ie, inability to fully extend); this may be an early sign of an inflammatory arthritis.
      • Palpate for soft tissue swelling of synovitis in fossae between the olecranon and lateral or medial epicondyles.
      • Assess for subcutaneous nodules in olecranon bursae and over the extensor surfaces of the elbow and forearm; these may represent rheumatoid nodules or tophi.
    • Shoulders
      • Evaluate the function of the entire shoulder complex. Observe the patient abduct both arms from 0° along side the body to 180° straight up. Assess external rotation by noting the position behind the neck or head to which the patient's hands can reach from above. Assess internal rotation by noting the highest level the dorsum of the patient's hands can reach in the back from below. A limitation of active shoulder motion should prompt an evaluation of passive motion.
      • Isolate and assess the motion of the glenohumeral joint. Abduction is checked with the patient's scapula fixed in place and the elbow flexed. The examiner uses one hand to prevent the spine or tip of the scapula from moving and then uses the other hand to abduct the patient's flexed arm. Normal glenohumeral abduction is 90°. External rotation is a movement mediated solely by the glenohumeral joint. It can be assessed by externally rotating the arm, flexed to 90° at the elbow and positioned either with the arm at the patient's side or in 90° of abduction. Limitation of glenohumeral motion is an indication of glenohumeral joint arthritis or capsular fibrosis.
      • Assess rotator cuff function. Observe the patient actively abduct the arm. Pain experienced at 60-100° of active abduction is an indication of supraspinatus tendonitis and/or subacromial bursitis.12
      • Spine: Assess the range of motion of the entire spine (ie, cervical, thoracic, lumbar).
      • For the cervical spine, ask the patient to touch the chin to the chest (flexion) and then look up at the ceiling (extension). For lateral flexion, ask the patients to touch an ear to their shoulder. For lateral rotation, ask patients to touch their chin to a shoulder. During lateral rotation and flexion, pain that occurs on the ipsilateral side of the neck is bony in origin (eg, apophyseal joint disease), while pain on the contralateral side is muscular or ligamentous in origin.
      • With the thoracic spine, restriction of chest expansion is a sign of ankylosing spondylitis. The circumference of the chest should be measured at the level of the nipples. A difference of less than 2.5 cm with inspiration is clearly abnormal.
      • For the lumbar spine, assess flexion, extension, and lateral flexion.13 Pain upon extension suggests pathology in the posterior elements of the spine (eg, facet joints or neurogenic compression seen with spinal stenosis). Pain upon flexion suggests disc disease. Lateral flexion is restricted early in the course of ankylosing spondylitis. Lumbar spine flexion is measured reproducibly with the Schober test. With the patient erect, make a horizontal mark at the level of the sacral dimples and make a second mark over the spine at a distance 10 cm above the first mark. Have the patient bend forward in an attempt to touch the floor. The distance between the 2 marks is measured in flexion. Normally, the distance should increase from 10 cm to more than 15 cm. Restriction of lumbar spine flexion can be seen with muscle spasm and ankylosing spondylitis. More severe restriction of motion (eg, result less then 2 cm) without acute lumbar pain is a reliable sign of ankylosing spondylitis.
      • Hips
      • Perform the log-rolling test. With the patient's leg in extension, the examiner gently rolls the entire limb back and forth. Limitation of internal or external rotation (particularly when compared to the contralateral hip) or groin pain is suggestive of true hip pathology.
      • The Thomas test helps assess for hip flexion deformity. The opposite hip is fully flexed as a means to flatten the lumbar lordosis and fix the pelvis. If the knee of the involved side is observed to elevate off the examining table, then an ipsilateral hip flexion deformity is present. This may be an indication of hip arthritis or tight hip flexor muscles.
      • For the Trendelenburg test, the patient is asked to stand and bear weight on only the involved leg. If the contralateral pelvis drops below level, then weakness of the hip abductors (ie, gluteus medius) is present on the affected side. Weakness of the hip abductors is a sign of hip arthritis. It can also have a neurogenic (eg, L5 root disease) or myogenic cause.
    • Knees14
      • Assess for synovitis. Visually inspect the knee for swelling and erythema; compare the affected knee with the contralateral knee. Palpate for warmth. Compare the temperature of the affected knee with that of the contralateral knee. The examiner should gently pass his or her hand from the patient's mid thigh or mid calf to the knee, assessing for a warmer temperature over the knee.
      • Assess for synovial effusion by eliciting the bulge sign and performing ballottement. The bulge sign test is performed with the patient supine, quadriceps relaxed, and knee fully extended. A small effusion, if present, is displaced from the medial side of the knee by stroking with the examiner's thumb. Its return is facilitated by quickly tapping the lateral side with the ends of the examiner's fingers and is observed as a gradual filling out of the recess created by stroking. Repeat the process several times in quick succession to be confident of the result. Ballottement is useful for detecting large knee effusions. With the patient's knee relaxed and fully extended, cup both hands around the knee, bringing the knee effusion into the central portion of the synovial cavity. Using the right index finger, push the patella straight down and release it quickly. The presence of a patellar tap, felt as the patella knocks against the underlying femoral condyles, is indicative of an effusion.
      • Assess range of motion. Synovitis with or without a synovial effusion may result in a decrease in the range of motion, including a loss of full extension (flexion deformity) and/or a reduction in flexion.
      • Assess for joint damage. Palpate the knee for crepitus with passive movement. Palpate the patella for crepitus as the patient actively extends the knee from a flexed position.
      • Assess for joint laxity. Test for lateral instability by attempting to adduct and abduct the lower leg with the knee held in 15° of flexion. Test for anteroposterior instability by attempting to push and pull the lower leg backward and forward with the knee held in 30° of flexion (Lachman test). Observe the alignment of the knee with the patient standing and bearing weight on both knees. Observe the back of the knee for popliteal or Baker cysts.
    • Ankles
      • Palpate for tenderness and soft tissue swelling over talar, subtalar, and midtarsal joints.
      • Assess range of motion of the talar (ie, with dorsiflexion, plantar flexion) and subtalar (ie, with inversion, eversion) joints.
    • Feet
      • Squeeze the row of metatarsophalangeal joints, assessing for the presence of pain or tenderness.
      • Palpate the small joints of the feet, assessing for the presence of tenderness, bony or soft tissue swelling, or joint effusion.

Differential Diagnoses

Other Problems to Be

  • Acute monoarthritis15
    Septic Arthritis16
    Gout and Pseudogout4
    Systemic rheumatic disease manifesting as monoarticular involvement
    Juxta-articular fracture
    Chronic monoarthritis
    Chronic infectious arthritis (see Septic Arthritis)
    Lyme Disease
    Crystalline synovitis (see Gout and Pseudogout)
    Pauciarticular juvenile rheumatoid arthritis (RA; see Rheumatoid Arthritis)
    Systemic rheumatic disease presenting with monoarticular involvement
    Ischemic necrosis (see Avascular Necrosis)
    Paget disease involving the joint (see Paget Disease)
    Stress Fracture
    Metastatic tumor
    Synovial osteochondromatosis
  • Acute polyarthritis
    Rheumatic fever (see Acute Rheumatic Fever)
    Gonococcal Arthritis
    Polyarticular gout (see Gout)
    Polyarticular pseudogout
    Viral arthritis (eg, hepatitis B infection, parvovirus B-19 infection)
    Bacterial endocarditis (see Infective Endocarditis)
    Rheumatoid Arthritis
    Still disease
    Systemic Lupus Erythematosus17
    Reactive Arthritis18
    Acute sarcoid arthritis
    Mediterranean Fever, Familial
    Enteropathic Arthropathies
  • Chronic polyarthritis
  • Shoulder
    • Referred pain
      • This is inflammation of the rotator cuff tendons, arising acutely as a result of a recognizable injury (throwing) or insidiously as a result of repeated impingement on the overlying acromion, coracoacromial ligament, acromioclavicular joint, or coracoid.
      • The principal symptom is pain in the deltoid region of the shoulder, aggravated by an overhead motion of the arm. The patient may also describe shoulder pain when sleeping on the affected side.
      • Examination findings include (1) tenderness in the subacromial region, between the greater tubercle of the humerus and acromial process; (2) pain in the mid arc of active abduction, usually 60-120°; (3) reproduction of pain when midarc abduction and external rotation are resisted isometrically; and (4) range of passive shoulder abduction exceeding that of active abduction.
      • Treatment includes avoidance of overhead reaching, nonsteroidal anti-inflammatory drugs (NSAIDs) for 2-3 weeks, and physical therapy with stretching and strengthening exercises. Subacromial corticosteroid injections may be used if symptoms do not improve.
    • Rotator cuff tear (see Rotator Cuff Injuries)
      • These are transverse or longitudinal tears of the supraspinatus or infraspinatus tendons. They occur at the musculotendinous juncture, approximately 1 cm from their insertion on the humerus.
      • They may arise as a result of an acute injury (eg, fall on an outstretched arm, hyperabduction, fall onto the side of the shoulder) or gradual attrition in the setting of chronic rotator cuff tendonitis.
      • With acute injury, symptoms include sharp shoulder pain followed by weakness of abduction. In the setting of chronic rotator cuff tendonitis, a tear is signaled by weakness of abduction or loss of smooth motion during abduction.
      • Examination findings include weakness and pain in the mid arc of abduction and external rotation and a loss of smooth overhead reaching (partial tear) or an inability to reach overhead (complete tear).
      • Initial management is conservative. Young patients with acute tears should be evaluated by an orthopedic surgeon.
    • Bicipital Tendonitis
      • This is inflammation of the long head of the biceps muscle as it passes through the bicipital groove of the anterior humerus.
      • It usually arises as a result of overuse with activities that require repetitive lifting.
      • The primary symptom is pain in the anterior aspect of the shoulder (over the humeral head), which is aggravated by lifting or overhead pushing or pulling.
      • Examination findings include tenderness of the bicipital groove and pain aggravated by isometric resistance to elbow flexion or supination of the arm flexed to 90°.
      • Treatment includes elimination of lifting, avoidance of over-the-shoulder reaching, and NSAIDs for 3-4 weeks. A corticosteroid injection of the bicipital groove can be given if symptoms persist.
    • Subacromial bursitis
      • This is the accumulation of fluid within the subacromial bursa, arising as a result of rotator cuff tendonitis. Significant fluid may be detected during a physical examination.
      • Treatment is similar to that for rotator cuff tendonitis. A significant effusion can be drained, followed by corticosteroid instillation.
    • Frozen shoulder (adhesive capsulitis)
      • This refers to conditions in which the range of motion of the glenohumeral joint is significantly reduced as a result of pathology within the joint capsule.
      • Primary symptoms are pain and gradual loss of shoulder motion without any known injury.
      • Associated medical conditions include diabetes mellitus, recent myocardial infarction, stroke, recent neurosurgical procedure, Parkinson disease, and hypothyroidism.
      • Examination findings include a reduced range of motion during both active and passive motion. Pain is present particularly at the extreme ranges of motion.
      • Radiographic images do not show evidence of glenohumeral arthritis.
      • The initial treatment regimen includes NSAIDs, nonnarcotic analgesics, and physical therapy. Occasionally, a 2- to 4-week course of oral corticosteroids combined with aggressive physical therapy may result in decreased pain and increased shoulder motion.
    • Acromioclavicular syndrome (see Acromioclavicular Joint Injury)
      • Pain arises from the acromioclavicular joint as a result of arthritis or injury to the acromioclavicular ligaments.
      • Osteoarthritis of the acromioclavicular joint with inferior osteophytes can lead to rotator cuff impingement and associated tendonitis.
      • This injury may be acute or chronic, and patients may report a history of trauma (eg, fall during a contact sport).
      • Examination findings include tenderness and swelling of the acromioclavicular joint. Deformity of the joint may result from subluxation.
      • Pain in the joint is aggravated by downward traction of the ipsilateral arm or forced passive adduction.
      • An acute acromioclavicular injury is treated with a shoulder immobilizer.
  • Elbow, wrist, and hand
    • Lateral Epicondylitis (tennis elbow)
      • This is the most common cause of elbow pain.
      • Pain is felt along the lateral aspect of the elbow.
      • Tenderness is present over the lateral epicondyle at the attachment of the extensor tendons of the forearm.
      • Resisting wrist dorsiflexion with the elbow in extension produces increased pain. Elbow extension is normal.
      • Treatment includes rest, NSAIDs, and local steroid injections.
    • Medial Epicondylitis(golfer elbow)
      • This condition is less common than lateral epicondylitis.
      • Resisted wrist flexion with the elbow in extension produces pain.
      • Tenderness may occur at the insertion of the common flexor tendon at the medial epicondyle.
    • Olecranon Bursitis
      • The anatomically superficial position of this bursa predisposes it to injury and inflammation.
      • The patient reports pain when leaning on the elbow and during flexion.
      • Examination findings include tenderness at the tip of the olecranon process and an occasional friction rub. Visible swelling of the bursa may be evident. In acute cases, warmth and erythema are present.
      • Acute bursitis must undergo aspiration for culture and crystal examination.
    • De Quervain Tenosynovitis
      • This is a stenosing tenosynovitis of the abductor pollicis longus and extensor pollicis brevis tendons, resulting from repetitive motion or overuse.
      • Pain is noted along the radial aspect of the wrist and thumb during pinching, grasping, and similar movements.
      • Ulnar deviation of the wrist, with the thumb held in abduction by the flexed fingers of the same hand (Finkelstein test) reproduces the pain. Crepitus of the tendons may be evident.
      • Treatment includes use of a thumb spica splint, avoidance of repetitive thumb flexion or abduction, and NSAIDs.
    • Trigger finger and trigger thumb (see Trigger Finger)
      • This condition is also known as stenosing digital tenosynovitis, snapping finger, and snapping thumb.
      • Injury is the result of overuse.
      • Examination findings include pain and tenderness and snapping, triggering, or catching during movement of the finger or thumb. A nodule is felt in the palm on the flexor tendon just proximal to the digital-palmar crease.
  • Hip
    • Referred pain
      • Pain in the posterior aspect of the hip is often referred from the lumbar spine.
      • Sacroiliac disorders can also cause buttock pain.
      • Pain from arthritis of the thoracolumbar junction may be referred pain to the area of the greater trochanters and may mimic trochanteric bursitis.
      • Radiculopathies of the L2-L4 nerve roots may produce pain in the inguinal area and the anterior aspect of the thigh. This may mimic hip disease.
      • Iliopsoas abscesses, retroperitoneal appendicitis, tuberculous abscesses, or pelvic inflammatory disease can be a cause of pain in the hip region.
      • Thrombosis or aneurysm formation in the branches of the aorta or iliac vessels may produce buttock, thigh, or leg pain that may be confused with hip pain.
      • True intra-articular hip pain is most often felt in the groin and anterior thigh. Occasionally, hip disease can manifest with isolated knee pain.
    • Trochanteric Bursitis
      • This is the most common cause of pain in the hip region (felt over the lateral aspect of the hip).
      • Pain increases with activities such as walking, squatting, and climbing stairs; pain typically decreases at rest. Patients note increased pain when lying on their ipsilateral side. The pain may be associated with a limp.
      • The area over the greater trochanter may be tender and boggy. Resisted abduction of the hip reproduces the pain.
      • Local corticosteroids with anesthetics may help.
    • Iliopsoas bursitis
      • This condition can occur in patients with osteoarthritis, RA, pigmented villonodular synovitis, osteonecrosis, and septic arthritis.
      • Most patients are asymptomatic or present with a painful inguinal mass.
      • CT scan is the best diagnostic test.
      • The instillation of corticosteroids is effective therapy.
    • Ischiogluteal bursitis
      • This occurs most commonly in patients with occupations that favor repeated friction of the ischial bursa.
      • Patients note pain over the ischial tuberosities; the pain is aggravated by sitting and lying down.
      • Local tenderness of the ischial tuberosities is found upon palpation
      • Symptoms may be alleviated by avoiding pressure or friction on the ischial tuberosities (ie, with the use of doughnut-shaped cushions) and local instillation of corticosteroids.
    • Adductor tendinitis
      • This disorder occurs in patients engaged in sports activities that involve straddling (eg, horseback riding, gymnastics, dancing).
      • Pain is typically felt in the groin and inner aspect of the thigh.
      • Tenderness can be elicited by local palpation of the adductor muscles, especially near their insertion on the front of the pelvis. Pain is increased by passive abduction of the thighs and active adduction against resistance.
      • Treatment consists of rest and ice packs during the acute phase. NSAIDs, ultrasonography, and progressive stretching exercises are used in the subacute phase.
      • Local corticosteroid injections are reserved for patients resistant to these conservative modalities.
  • Knee and ankle
    • Prepatellar Bursitis (housemaid knee)
      • This condition is related to recurrent trauma and usually occurs in persons who spend significant time kneeling.
      • In chronic cases, a well-circumscribed area of fluctuance is present over the prepatellar area. In acute cases, warmth, edema, and erythema are noted over the anterior knee. Fluctuance may be subtler. Tenderness is maximal over the prepatellar bursa. Knee flexion increases the pain, whereas knee extension does not. A joint effusion, if present, is small.
      • Etiologies include trauma, gout, and infection.
      • Aspiration of acute bursitis is necessary to assess for the presence of an infection or crystals.
      • Traumatic bursitis improves with rest and avoidance of kneeling.
    • Anserine bursitis (see Pes Anserinus Bursitis)
      • Pain is noted over the medial aspect of the knee, is made worse by climbing stairs, and is often present at night.
      • It is most common in overweight women with osteoarthritis of the knees.
      • Examination reveals exquisite tenderness over the anserine bursa, located over the medial aspect of the knee approximately 2 inches below the joint line.
      • Treatment includes a corticosteroid injection into the bursa and an exercise regimen to stretch the adductor and quadriceps muscles.
    • Patellar tendonitis (jumper's knee)
      • Most commonly, this affects young athletes who are engaged in sports that require repetitive running, kicking, and jumping.
      • Pain is noted at the inferior pole of the patella during activities such as climbing stairs, running, and jumping.
      • Treatment consists of rest, NSAIDs, knee bracing, and an exercise regimen to stretch and strengthen the quadriceps and hamstring muscles.
    • Achilles tendonitis (see Achilles Tendon Injuries and Tendonitis)
      • Pain, swelling, tenderness, and crepitus are noted over the tendon near its insertion.
      • This form of tendonitis is usually caused by repetitive trauma and microscopic tears due to excessive use of the calf muscles in ballet dancing, distance running, basketball, jumping, and other athletic activities. Faulty footwear with a rigid shoe counter also may produce Achilles tendonitis.
      • Examination findings include thickening and irregularity of the tissues surrounding the tendon and palpable nodule(s) within the tendon (occasionally representing xanthomata, tophi, or rheumatoid nodules). Passive dorsiflexion of the ankle intensifies the pain.
      • Abnormalities of the tendon and peritendinous tissues can be demonstrated on images from ultrasonography and MRI studies.
      • Treatment consists of rest, avoidance of the provocative occupational or athletic activity, shoe modification, a heel lift to reduce tendon stretching during walking, and NSAIDs. Physical therapy includes local heat application, gentle stretching exercises, and a temporary splint with slight plantar flexion.
    • Retrocalcaneal bursitis (see Achilles Tendon Injuries and Tendonitis)
      • This is inflammation of the retrocalcaneal bursa, resulting in pain and tenderness at the back of the heel.
      • The area anterior to the Achilles tendon and posterior to the calcaneus is tender; passive dorsiflexion of the ankle produces pain.
      • Bursal distension is palpable and produces bulging on both sides of the tendon.
      • This may occur as a result of repetitive trauma or as a manifestation of gout or a systemic inflammatory arthritis.
      • Diagnosis can be confirmed based on radiography (obliteration of the retrocalcaneal recess), ultrasonography, or MRI findings.
      • Rest, activity modification, moist heat application, slight heel elevation using a felt heel pad, and NSAIDs constitute sufficient therapy for most patients.
      • A walking cast or cautious corticosteroid injection into the bursa is sometimes required.


Laboratory Studies

  • Most useful diagnostic tests for specific rheumatic diseases20
    • Septic arthritis: Order a Gram stain and culture of synovial fluid.6,21
    • Gout or pseudogout: Use compensated polarized light microscopy to examine a drop of synovial fluid for intracellular urate (gout) or calcium pyrophosphate dihydrate (pseudogout) crystals.
    • Ankylosing spondylitis: Obtain sacroiliac joint radiographs to demonstrate bilateral sacroiliitis.22
    • Osteoarthritis: Obtain radiographic images of the affected joint.
    • Systemic lupus erythematosus (SLE): Screen with an antinuclear antibody (ANA) test. If positive, test for Smith (Sm) and double-stranded DNA antibodies. These antibodies are more specific for SLE but are present in only 30-60% of patients with SLE, respectively.23
  • Screening tests for all types of inflammatory arthritis24
    • Erythrocyte sedimentation rate (ESR): In the setting of joint pain and equivocal joint examination findings, an elevated ESR supports the presence of an inflammatory arthritis.
    • C-reactive protein (CRP): This test is a nonspecific measure of inflammation and is an alternative to obtaining the ESR. In contrast to the ESR, the CRP level (1) can be measured on frozen serum, (2) is not influenced by the presence of anemia or hyperglobulinemia, (3) rises more rapidly in response to an inflammatory stimulus, and (4) may require more time for the laboratory result to be available (ie, 1 h for ESR; >24 h for CRP).
    • Rheumatoid factor and cyclic citrullinated peptide (CCP): A rheumatoid factor test should be obtained when rheumatoid arthritis (RA) is at least moderately possible in the patient. Results may be positive in up to 20% of healthy elderly persons and in persons with other rheumatic diseases (eg, SLE, Sjögren syndrome, vasculitis), chronic infections (eg, subacute bacterial endocarditis, hepatitis C), chronic liver disease, or chronic lung disease. Measuring antibodies to CCP is a new test for RA; it has higher specificity but lower sensitivity than rheumatoid factor. The CCP antibody test is particularly useful in the evaluation of a patient with joint pain whose rheumatoid factor is of low titer and whose findings on joint examination are not definitive for synovitis.
    • ANAs: ANA tests are commonly obtained in patients with arthralgias or arthritis as a screening test for SLE or another connective-tissue disorder.23 More than 95% of patients with SLE have ANAs; thus, a negative ANA result is a strong indicator that SLE is not present. However, a positive ANA result lacks specificity and may occur in persons with other connective-tissue diseases or certain medical illnesses or in 5-10% of otherwise healthy individuals. The diagnostic yield of the ANA test is increased substantially when the patient has features that suggest a diagnosis of SLE or another autoimmune disease in addition to joint pain. These include a photosensitive skin rash, pleuritis, pericarditis, Raynaud phenomenon, constitutional symptoms (eg, fever), leukopenia, thrombocytopenia, sicca symptoms, and proteinuria.
  • Screening tests for acute polyarthritis
    • Blood cultures
    • Antistreptolysin O titer
    • Parvovirus B-19 immunoglobulin G and immunoglobulin M levels
    • Hepatitis B serology
    • ANAs
    • Others to consider: These may include an HIV test, a rubella titer, an angiotensin-converting enzyme level and chest radiograph, and antineutrophil cytoplasmic antibody testing.
  • Screening tests for chronic polyarthritis
    • Complete blood cell count
    • ESR and CRP level
    • ANAs
    • Rheumatoid factor and CCP antibody
    • Chemistry profile, including liver function tests and a serum creatinine level
    • Serum uric acid level
    • Urinalysis
    • Others to consider: These include a thyroid-stimulating hormone level, a serum ferritin level, and an iron saturation of serum transferrin.
  • Screening tests for diffuse arthralgias and myalgias
    • ESR and CRP level to exclude inflammatory disease, including polymyalgia rheumatica
    • Creatine kinase and aldolase level to exclude myositis
    • Thyroid testing
    • Chemistry profile (ie, calcium, phosphorus, electrolyte, glucose, total protein) to exclude metabolic or endocrine disorders
    • Others to consider: These include a 25-hydroxy vitamin D level (in elderly housebound individuals to exclude osteomalacia), sacroiliac joint radiography (to exclude ankylosing spondylitis, especially in woman <45>

Imaging Studies

  • Choice of imaging modality
    • Plain radiography: This is the least expensive imaging modality and is most useful for clarifying the nature of joint abnormalities already noted during the physical examination (eg, swelling [bony vs soft tissue], loss of motion [bony vs soft tissue], instability [ligamentous vs destruction of articular surface], focal bony tenderness [fracture vs osteomyelitis]).25 The appearance of joints on plain radiographs is often distinctive for various forms of arthritis (see Plain radiographic findings in various arthritides, although these characteristic changes may not be apparent early in the disease course. Plain radiographs are useful for monitoring the progression of chronic arthritides (eg, osteoarthritis, RA).
    • CT scan: This technique obtains cross-sectional images of skeletal structures.26 It is most useful for (1) assessing trauma of the spine and pelvis, (2) evaluating arthritis in axial joints (eg, sacroiliac, atlantoaxial, sternoclavicular), (3) evaluating pain in complex joints in which overlying structures obscure plain radiography views (eg, ankle, wrist, temporomandibular joints), and (4) evaluating degenerative disc disease of the spine and possible disc herniations.
    • MRI: This imaging modality is the best for assessing soft tissue and spinal cord elements.26 It is of greatest use for assessing rotator cuff tears, spinal stenosis, ligamentous or meniscal abnormalities of the knee and wrist joints, osteonecrosis (ie, avascular necrosis of bone), stress fractures, osteomyelitis, and subchondral bone injury in osteoarthritis or meniscal tears.
    • Arthrography: It is of greatest use for defining abnormal communication between the synovial space and adjacent bursae and soft tissue (ie, popliteal cysts, rupture of rotator cuff with communication between glenohumeral joint space and subacromial bursa).
    • Radionuclide bone scanning: This is widely available, and the cost is comparable to that of a CT scan. It is most useful for assessing osteomyelitis, stress fractures, and bony metastasis. It may be used to exclude skeletal disease in patients with diffuse musculoskeletal pain.
  • Plain radiographic findings in various arthritides22
    • Rheumatoid arthritis
      • Early changes include soft tissue swelling and periarticular demineralization.
      • Later changes include uniform loss of joint space (indicative of diffuse cartilage loss) and bony erosions (initially along joint margins where intra-articular bone is not covered by cartilage).
      • Advanced changes include diffuse bony erosions, joint subluxation, and foreshortening of digits. Ankylosis of joints is rare.
    • Psoriatic arthritis
      • Early changes include soft tissue swelling, occasionally involving the entire digit (ie, sausage digit), and an absence of periarticular demineralization.
      • Later changes include erosions coupled with reactive new bone formation, initially at joint margins and later within the center of the joint. Other late changes are uniform joint space narrowing and ankylosis of involved joints.
      • Advanced changes are joint space widening in interphalangeal joints caused by severe destruction of marginal and subchondral bone, resorption of tufts of distal phalanges of fingers and toes, arthritis mutilans (ie, severe joint destruction with extensive bone resorption), and the pencil-in-cup deformity.
      • Distinctive features are involvement of the distal interphalangeal joints, a tendency for early ankylosis, asymmetric joint involvement, and abnormalities of phalangeal tufts.
    • Reactive arthritis
      • Radiographic features are similar to psoriatic arthritis, but they are often less severe and have a predilection for lower extremity joints.
      • Distinctive features include a predilection for lower extremities (eg, knees, ankles, feet), a tendency for unilateral or asymmetric sacroiliitis, paravertebral ossification, and calcaneal erosions and/or periostitis at sites of Achilles tendon and plantar fascia insertion.
    • Gout
      • Acute gouty arthritis is indicated by soft tissue swelling. Degenerative changes of the involved joint are common.
      • Intercritical gout does not manifest radiographic abnormalities, apart from possible degenerative changes in the joint.
      • Chronic tophaceous gout is indicated by soft tissue swelling, often asymmetric or outlining an eccentric nodular subcutaneous mass. The joint space may be preserved despite extensive erosions, a finding not expected in RA. Bone erosions are contiguous with tophi and are characterized by overhanging and sclerotic margins. Osteolytic bone lesions occur near joints. Periarticular demineralization is absent or mild, except late in the disease course.
    • Calcium pyrophosphate dihydrate crystal deposition disease
      • Radiographic evidence of calcium crystal deposition in articular structures is seen most often in the knee, symphysis pubis, wrist, elbow, and hip. The prevalence increases with age, and it is often an incidental finding and not often associated with joint symptoms. Hyaline cartilage calcification is fine and linear, and it follows the contour of the underlying subchondral bone. Fibrocartilage calcification is coarse and irregular, and it is often seen in knee menisci, triangular fibrocartilage and the meniscus of the wrist, and the symphysis pubis. Synovial calcification is amorphous and usually occurs at sites of synovial reflection. Capsular calcification is linear deposits bridging the peripheral joint margins. Extra-articular calcification occurs in tendons, ligaments, and para-articular soft tissues.
      • Pyrophosphate arthropathy is a distinctive arthropathy that may occur in patients with calcium pyrophosphate dihydrate crystal deposition disease. Radiographic findings are the same as those for osteoarthritis. Distinctive features include (1) involvement of joints not usually affected by osteoarthritis (eg, MCP, wrist, elbow, ankle, shoulder), (2) involvement of specific joint compartments (eg, radiocarpal and trapezioscaphoid joints of wrists, patellofemoral joint of knee, talocalcaneonavicular joint of midfoot), (3) prominent subchondral cysts, and (4) occasional articular destruction (resembling a neuropathic joint) with subchondral bone collapse and fragmentation and formation of intra-articular loose bodies.
    • Infectious arthritis
      • Early changes include symmetric soft tissue swelling, an absence of periarticular demineralization in an acute pyogenic arthritis, and joint space loss (although joint space widening may be seen initially because of fluid accumulation in a small joint space).
      • Later changes include marginal bone erosions. Also, the continuous white cortical line that normally defines the margin of articulating bone is lost; these changes are expected on both sides of the joint. A periosteal reaction occurs. Finally, gas formation within the joint and adjacent soft tissues can be seen with infections related to Escherichia coli, Enterobacter liquefaciens, and Clostridium perfringens.
      • Advanced changes include destruction of subchondral bone, intra-articular bony ankylosis, and subluxation or dislocation.
    • Osteoarthritis
      • Early changes include small osteophytes at joint margins, focal narrowing of joint spaces (more uniform joint space loss is noted in interphalangeal and MCP joints of the hands and sacroiliac joints), subchondral bony sclerosis in the segment affected by joint space loss, and an absence of periarticular demineralization.
      • Later changes include large and more extensive osteophytes at joint margins or at ligamentous attachments (eg, tibial spines), more pronounced focal joint space narrowing, subchondral bone cysts with sclerotic margins in the areas of joints affected by joint space loss, and the formation of bony ossicles (round or oval fragments of bone) in soft tissues adjacent to the joint or within the joint cavity.
      • Advanced changes include extensive joint space loss and joint deformity.

Other Tests

  • Synovial fluid analysis27
    • This test is used to broadly characterize the type of arthritis, to identify crystals, and to establish the diagnosis of septic arthritis and crystal-induced synovitis.27
    • Synovial fluid types are classified as normal, noninflammatory, inflammatory, septic, or hemorrhagic.
      • Normal: Characteristics include clear to pale yellow color, transparent clarity, WBC count of less than 200/µL with less than 25% polymorphonuclear (PMN) leukocytes, and very high viscosity.
      • Noninflammatory (group I): Characteristics include pale yellow color, transparent clarity, WBC count of 200-2000/µL with less than 25% PMN leukocytes, and high viscosity. It typifies osteoarthritis, traumatic arthritis, and an early or resolving stage of an inflammatory arthritis.
      • Inflammatory (group II): Characteristics include yellow-to-white color, translucent-to-opaque clarity, WBC count of 2000-50,000/µL with more than 70% PMN leukocytes, and low viscosity. It typifies RA and other chronic inflammatory arthritides.
      • Septic (group III): Characteristics include a white-to-cream color, opaque clarity, WBC count of more than 50,000/µL with more than 90% PMN leukocytes, and very low viscosity. It typifies bacterial arthritis, but it also may occasionally be seen in crystalline arthritis and flares of RA.
      • Hemorrhagic (group IV): Characteristics include a hemorrhagic color and opaque clarity. Fat globules should be sought in hemorrhagic fluids by centrifuging the synovial fluid. A supernatant of fat is indicative of a juxta-articular fracture.
    • A joint may be affected by more than a single process; thus, septic arthritis and gout or pseudogout may coexist in the same joint.
    • The synovial fluid WBC count may be lower in patients who are early in the course of septic arthritis or in patients with disseminated gonococcal infection.
    • Crystal analysis requires compensated polarized light microscopy, which is available in most diagnostic or pathologic laboratories.28 It is performed on a wet smear preparation of synovial fluid. Intracellular crystals in synovial fluid are required to establish a diagnosis of acute gout or pseudogout. Urate crystals are needle-shaped with strong negative birefringence. Calcium pyrophosphate dihydrate crystals are rhomboid-shaped with weak positive birefringence. Urate crystals appear yellow and calcium pyrophosphate dihydrate crystals appear blue when their long axes are aligned parallel to that of the red compensator filter.


  • In the majority of patients with rheumatic diseases, an accurate diagnosis can be established without performing a synovial biopsy. For certain conditions, histopathologic findings in the synovium are either pathognomonic or highly specific. These include various granulomatous arthritides (eg, tuberculous, fungal, sarcoidosis), amyloidosis, synovial tumors, ochronosis, hemochromatosis, and multicentric reticulohistiocytosis.
  • Medical Care
    Most patients who present with a new musculoskeletal complaint have a problem restricted to one anatomic region or joint. Examples include back or shoulder pain. These problems are usually recognized as self-limited and not of the type to pose a major hazard to the health of the patient. Such patients are treated symptomatically and advised about the optimal balance of activity and rest, the benign nature of the problem, and the expectation of healing in 2-6 weeks. Extensive testing is inappropriate because abnormalities may be revealed that are irrelevant, and these results may prompt further, often unnecessary, investigations. Clinical situations in which acute musculoskeletal symptoms must be evaluated promptly and thoroughly include (1) a severe condition involving one joint or, at most, a few joints; (2) a patient who is febrile, is systemically ill, or is showing signs of multiple organ involvement; (3) a problem associated with significant trauma; and (4) a condition in which an associated neurologic problem exists, such as carpal tunnel syndrome, sciatica, or cervical radicular symptoms.9

    In patients with arthritis, the goals of treatment include relief of pain, restoration or maintenance of joint function, and prevention of joint damage. These goals are achieved with both pharmacologic and nonpharmacologic therapeutic modalities. While some modalities are common to the treatment of all forms of arthritis, others are specific to certain forms of arthritis. Thus, proper treatment begins with an accurate diagnosis. One of the challenges in treating arthritis is determining the expected prognosis and instituting appropriate therapy in a timely fashion, thereby avoiding the development of irreversible joint dysfunction.

    The initial assessment of the patient should allow classification of the joint problem into one of the categories detailed below:

    Acute monoarthritis21,15
    Principles of management
    Hospitalize any patient with possible septic arthritis.
    Aspiration of joint fluid is a critical step in diagnosis.
    The finding of noninflammatory joint fluid in an acutely inflamed joint should prompt consideration of juxta-articular osseous pathology (eg, stress fracture, osteomyelitis, avascular necrosis), acute inflammation of periarticular structures (eg, gouty inflammation of tendon sheaths or bursae, septic bursitis), subcutaneous inflammation (eg, arthritis of ankles in erythema nodosum, pancreatic fat necrosis), or cellulitis.
    Initial treatment of possible septic arthritis6,29
  • Begin intravenous antibiotic therapy if the possibility of septic arthritis cannot be excluded with reasonable certainty after the initial clinical and laboratory evaluation.
    Provide for adequate drainage of the joint. Repeated percutaneous aspiration of the joint with a large-bore needle is indicated. Arthroscopic drainage of knees, shoulders, ankles, and elbows is an acceptable alternative, provided the risk of anesthesia is not excessive. Use surgical drainage for hips and for other joints that cannot be adequately drained with needle aspiration or that do not improve after 3-5 days of repeated percutaneous aspiration. Initial treatment of acute crystalline synovitis4
  • NSAIDs should initially be given at their maximum recommended dosage until symptoms improve. Then, they should be tapered gradually over several days. Indomethacin is very effective, but adverse effects in some patients limit its utility. Other NSAIDs with short half-lives (eg, ibuprofen, diclofenac) can also be used.
    Colchicine has a narrow therapeutic window, which limits its effectiveness. It must be used cautiously in the setting of renal insufficiency. Thus, its use to treat acute gouty arthritis (as opposed to low doses to prevent attacks) has been largely supplanted by other therapies.
  • Corticosteroids are an effective alternative to NSAIDs and colchicine for patients in whom these drugs may be contraindicated or hazardous (eg, patients with advanced age, renal insufficiency, congestive heart failure, inability to take oral medications). Regimens include (1) an intramuscular injection of a long-acting crystalline preparation (eg, triamcinolone acetonide at 60-80 mg), with an option to repeat once after 24-48 hours; (2) prednisone at 20-30 mg/d with a progressive taper over 7-10 days; and (3) intra-articular corticosteroid therapy.
  • Acute polyarthritis30
    Principles of management
    Hospitalize the patient in the presence of (1) significant, concomitant internal organ involvement; (2) signs of bacteremia, including vesiculopustular skin lesions, Roth spots, shaking chills, or splinter hemorrhages; (3) systemic vasculitis; (4) severe pain; (5) severe constitutional symptoms; (6) purulent (group III) synovial fluid in one or more joints; or (7) immunosuppression.
  • An infectious etiology should receive first consideration. Obtain appropriate cultures (eg, blood, joint, cervix, urethra, pharynx). Begin empiric antibiotic therapy if bacteremia or sepsis cannot be readily excluded.
  • Extra-articular manifestations, such as a rash, hematologic abnormalities, or heart murmur, should be sought as important indicators of the diagnosis.
  • Repeated examinations of the patient are required to detect diagnostic physical findings that may be absent at presentation.
  • Initial treatment modalities for patients with acute polyarthritis
    Antibiotic therapy is indicated for septic polyarthritis or bacteremia with joint involvement (eg, disseminated gonococcemia). Systemic antibiotics are used after appropriate cultures are taken. Prolonged treatment of reactive arthritis with antibiotics is not supported by current evidence.31
  • Analgesics without anti-inflammatory properties may be appropriate as the initial treatment in patients with milder forms of acute rheumatic fever, viral arthritis (eg, parvovirus arthritis), or acute leukocytoclastic vasculitis. They also may be appropriate for those with polyarticular crystalline synovitis in whom significant concomitant medical problems preclude the use of NSAID or corticosteroid therapy. This therapy allows for the complete expression of the clinical manifestations of the disease, thereby aiding in diagnosis.
  • High-dose aspirin therapy can be used for acute rheumatic fever, with the goal of achieving a salicylate level of 20-30 mg/dL. High-dose NSAID (nonsalicylate) therapy is used to treat crystalline synovitis, acute viral arthritis, and polyarthritis related to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or other connective-tissue disorders.
    Corticosteroids are used in persons with polyarthritis alone in whom high-dose NSAID therapy has failed or who cannot be treated safely with NSAIDs because of renal insufficiency, active GI bleeding, or other conditions. Prednisone at 15-20 mg/d (or equivalent) is usually sufficient for acute polyarticular flares of RA. High doses of prednisone (0.5-1 mg/kg/d) are used in the setting of severe constitutional symptoms, concomitant major organ involvement, or signs of systemic vasculitis. Examples include acute SLE, Still disease, or acute rheumatic fever that fails to respond to NSAID therapy.
  • Chronic (inflammatory) monoarthritis
  • Principles of management
    Diagnoses other than osteoarthritis should be considered if the patient has a synovial fluid WBC count of greater than 1000/µL, hemorrhagic synovial fluid, no significant radiographic changes associated with osteoarthritis, synovial proliferation, significant pain, or constitutional symptoms.
  • The initial diagnostic focus in a patient with a chronic inflammatory monoarthritis is always on a potential infectious etiology. (Lyme arthritis can manifest as a subacute or chronic inflammatory monoarthritis; its diagnosis is based on the results of serologic testing. Antibiotic treatment is indicated.)
  • Perform a synovial biopsy and culture if the initial evaluation (including synovial fluid cultures) fails to establish a specific diagnosis.
    Consider aseptic necrosis in a joint with noninflammatory joint fluid.
    Treatment modalities for patients with chronic (inflammatory) monoarthritis
    Chronic gout therapy requires allopurinol (the preferred drug) to correct hyperuricemia. Suppress chronic inflammation with NSAIDs, colchicine (eg, 0.6 mg bid), or both. Intra-articular corticosteroid therapy may also be appropriate.
    Other crystalline arthropathies (calcium pyrophosphate, hydroxyapatite) are treated by suppressing chronic inflammation with NSAIDs, colchicine, or both. Intra-articular corticosteroid therapy may also be appropriate.
    Monoarticular presentation of a systemic rheumatic disease is treated with systemic therapies appropriate to the rheumatic disease, particularly if intra-articular corticosteroids are contraindicated or ineffective for long-term suppression of the monoarticular disease.
  • Chronic (inflammatory) polyarthritis
    Principles of management
    Treatment with NSAIDs is often initiated before a firm diagnosis is established.
    Certain diagnoses should be sought during the initial patient evaluation because specific (and potentially curative) therapies are needed. These include chronic polyarticular gout, subacute bacterial endocarditis, and hepatitis C–related syndromes (eg, cryoglobulinemia, arthritis).
  • Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, leflunomide, and tumor necrosis factor-alpha antagonists should be started relatively early in the course of rheumatoid or psoriatic arthritis in order to prevent joint damage. Consultation with a rheumatologist is prudent in order to confirm these diagnoses and to initiate appropriate DMARD therapy.
  • Corticosteroids in low doses (≤10 mg) may serve as a valuable adjunct to the treatment of chronic inflammatory arthritides, although attention must be paid to the adverse effects of long-term steroid use (eg, osteoporosis).
  • Treatment modalities
  • NSAID choice is guided by the patient's comorbidities and past response to these drugs. It is also guided by the cost and dosing frequency of the drugs. Maximal doses of NSAIDs are generally required for effective management of chronic polyarthritides. However, lower doses may be used if the disease is being adequately suppressed with DMARDs.
    DMARDs are used to suppress synovitis and thereby prevent or at least retard the development of joint damage and/or deformity. The choice of DMARD regimen depends on a number of factors, including the underlying disease, comorbidities, and prior treatment responses, among others. Guidelines for the use of DMARDs in various polyarthritides are presented in other eMedicine articles (eg, see Rheumatoid Arthritis).
  • Osteoarthritis
    Principles of management
    Management is most effective when it includes physical measures to reduce joint loading, an appropriate exercise regimen, medications, and, occasionally, surgery.
    The natural history of osteoarthritis is punctuated by episodes of more intense joint pain, followed by long periods of relative quiescence. More persistent, chronic pain is a feature of advanced disease. Dosing of anti-inflammatory and analgesic medications should be calibrated to the severity of the joint pain. Acute episodes may require enforced joint rest for relief; use of crutches, a cane, splints, or other orthotic devices; and strict avoidance of certain activities.
  • Prevention of symptomatic flares is key to proper management. Patients should be educated to maintain or achieve ideal body weight, exercise to strengthen muscles that support diseased joints, and avoid specific activities that aggravate joint pain (eg, stair climbing, strenuous exercise, throwing, kneeling).
  • Nonpharmacologic management
  • Instruct the patient to attempt to achieve and/or maintain ideal body weight.
    Teach the patient joint preservation techniques.
    Recommend a physical therapy regimen that includes range-of-motion and flexibility, conditioning, and aerobic cardiovascular exercises.
    Prescribe orthotic devices (eg, cane, walker, splint, wedged insoles) to rest or unload a joint.
    Recommend the use of devices to assist activities of daily living (eg, tub seat, elevated toilet, dressing sticks, long-handled shoe horns).
    Pharmacologic management32,33
    Mild disease can be treated with acetaminophen (up to 1 g qid); tramadol (50-100 mg qid); over-the-counter NSAIDs (eg, naproxen, ibuprofen) in analgesic doses; glucosamine (500 mg tid); or topical analgesics containing capsaicin, methylsalicylate, or an NSAID.
    Moderate disease is treated with NSAIDs. Persistent symptoms not relieved by mild therapy often require NSAID administration for prolonged periods in anti-inflammatory doses. In this setting, give careful consideration to potential NSAID toxicities. Avoid long-term use of indomethacin, piroxicam, and mefenamic acid. Use of the COX-2 inhibitor, celecoxib, is associated with a lower frequency of serious GI complications. Celecoxib is an option for patients with a history of peptic ulcer disease or previous upper GI bleeding and for those taking anticoagulants or oral corticosteroids. It should be avoided in patients with significant cardiovascular disease or risk factors. The risk of NSAID gastropathy can be reduced by coadministering a proton pump inhibitor.
  • Intra-articular hyaluronan may provide relief of symptomatic knee osteoarthritis for periods up to 1 year. It requires a series of 3-5 weekly injections. Intra-articular corticosteroids are beneficial for patients with symptomatic effusions. Use is limited to 1 injection per joint every 3 months.
    Severe disease is the presence of intractable pain and/or significant incapacity, and this is an indication for surgical intervention. Opiate analgesics may be used for intractable pain, but first thoroughly consider the risks associated with their long-term use.
    Soft tissue rheumatic pain disorder
    Principles of management of regional musculoskeletal pain syndromes (eg, tendonitis, bursitis, acute soft tissue injuries, and regional myofascial pain syndromes)11
    Allow the soft tissue injury to heal with a short period of enforced rest. This can be achieved with immobilization or avoidance of activities that require the use of the involved part.
  • Provide pain relief using both nonpharmacologic (eg, local heat or cold, electrical stimulation, massage) and pharmacologic (eg, oral analgesics, NSAIDs, muscle relaxants, corticosteroid injections, topical agents) modalities.
    Prescribe an exercise program to be performed at home or under the guidance of a physical therapist. The goals should include stretching, muscle strengthening, and education about proper body mechanics.
  • Identify and eliminate factors that have aggravated or precipitated soft tissue pain (eg, posture, repetitive trauma, poor body mechanics).
    Principles of management of generalized noninflammatory soft tissue rheumatic pain syndromes (eg, fibromyalgia, hypermobility syndrome)
    Screen for coexistent depression, and treat it if present.
    Screen for a sleep disorder, and treat it if present.
    Emphasize the primary role of low-level aerobic exercise in treatment.
    Treat pain using agents that are acceptable for prolonged use and do not promote physical dependence.

  • Surgical Care
    Indications for surgical management of arthritis include the following:

    Uncertain diagnosis: Perform a synovial or bone biopsy.
    Acute septic arthritis6
    Drain hip and shoulder joints.
    Surgically drain joints that are not responding to repeated percutaneous needle drainage.
    Remove hardware or exchange polyethylene components in an infected prosthesis.
  • Rheumatoid arthritis
    Perform total arthroplasty on large joints, such as hips, knees, and shoulders. The primary indication is relief of pain that has failed to improve with medical therapy. Improvement of function and motion are secondary goals that are not always attainable.
    Perform wrist synovectomy and dorsal hand tenosynovectomy for persistent synovitis of the dorsum of the wrist and hand that threatens tendon integrity.
    Correct atlantoaxial or subaxial subluxation in the cervical spine.
    Perform reconstructive surgery of the hands and feet.
  • Osteoarthritis
    Use arthroscopic surgery to correct internal derangements (eg, meniscal tears) and to remove loose bodies that are causing mechanical symptoms.
    Perform an osteotomy to distribute weight in the compartment of a joint with relatively preserved cartilage.
    Total arthroplasty is indicated to relieve the pain of advanced joint disease; improvement of function and motion are secondary goals.
    Joint fusion is indicated on joints such as the ankle (eg, triple arthrodesis) or carpometacarpal joints in order to relieve pain and instability.


    Patient Education

    For excellent patient education resources, visit eMedicine's Hand, Wrist, Elbow, and Shoulder Center. Also, see eMedicine's patient education article Tennis Elbow.

    Differential Diagnoses & Workup
    Treatment & Medication