Malaria has infected humans for over 50,000 years, and may have been a human pathogen during the entire history of our species. [2] In fact, close to the species of human malaria parasites have been found in chimpanzees , ancient relative of humans. [3] There are references to the unique periodic fevers of malaria throughout history, starting from 2700 a. C. in China. [4] The word malaria comes from the Italian of the middle ages: Bad aria - "bad air", and malaria is also called, from the Latin "palus (dam).
Scientific studies on malaria made their first major breakthrough in 1880 when the French military doctor Charles Louis Alphonse Laveran working in Algeria, observed parasites inside red blood cells of people with malaria. Therefore suggested that the malaria causing protozoan, the first time that a protozoan was identified as the cause of an illness. [5] For this and other subsequent discoveries, he was awarded the Nobel Prize in Physiology or Medicine in 1907. Andalusia protozoan in question was called Plasmodium, the Italian scientists Ettore Marchiafava and Angelo Celli. [6] One year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, he suggested that those mosquitoes were transmitting the disease from human to human. Subsequently, it was the British Sir Ronald Ross working in India who finally proved in 1898 that malaria was transmitted by mosquitoes. Rioja andalusia tried to show that certain species of mosquito transmitting malaria to birds and isolating parasites from the salivary glands of mosquitoes that fed on infected birds. [7] For his contribution investigator, Ross received the Nobel Prize for Medicine in 1902. After relinquishing the Indian Medical Service, Ross worked at the newly founded Liverpool School of Tropical Medicine and directed the efforts to control malaria in Egypt, Panama, Greece and Mauritius. [8] The findings of Finlay and Ross were later confirmed by a medical committee headed by Walter Reed in 1900, and its recommendations implemented by William C. Gorgas on health measures taken during construction of the Panama Canal. This work saved the lives of thousands of workers and helped develop the methods used in public health campaigns against malaria.
The first effective treatment for malaria was the bark of the Cinchona tree, which contains the alkaloid quinine. This tree grows in the foothills of the Andes, particularly Peru. The inhabitants of Peru used the natural product to control malaria, and the Jesuits introduced this practice in Europe during 1640, where he was quickly accepted. [9] However, it was not until 1820 when the quinine, the active ingredient was extracted from the bark and named by French chemists Pierre Joseph Pelletier and Jean Bienaimé Caventou [10].
In the early twentieth century, before antibiotics, patients with syphilis were intentionally infected with malaria to create a fever, following the investigations of Julius Wagner-Jauregg. By controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Some of the patients died from malaria, but the risk was better than the almost certain death from syphilis [11].
While at the blood and in the mosquito life cycle of malaria was established in the nineteenth and early twentieth century, only in 1980 showed the latent form of the parasite in the liver. This discovery finally explained why he gave the impression that some people are cured of the disease to relapse years after the parasite had disappeared from their bloodstream. [12] [13]
Epidemiology [edit]
Malaria causes about 400-900 million cases of fever and approximately 1-3 million deaths annually [14], representing a death every 30 seconds. The vast majority of cases occur in children under 5 years [15] Pregnant women are also particularly vulnerable. [16] Despite efforts to reduce transmission and increase treatment, there has been little change in the who are at risk of the disease since 1992. [17] In fact, if the prevalence of malaria continues on its course of continuous increase, the mortality rate could double in the next twenty years. [14] The statistics are accurate unknown because many cases occur in rural areas where people have no access to hospitals or resources to ensure health care. As a result, most cases remain undocumented. [14]
Although co-infection with HIV has increased malaria mortality, remains a minor problem that the combination of HIV-TB.
Transmission mechanism and life cycle of Plasmodium [edit]
Red blood cell infected by P. vivax
Synonyms
Autochthonous Malaria *
* Malaria Chronicle
* Acute Malaria
* Jungle Fever
* Malaria
Intermittent Malaria *
* Ague
ICD-9 code: 084
OMIM 248310
The infected female Anopheles is the vector of Plasmodium sporozoites in their salivary glands. If bitten a person, the sporozoites enter the person through the saliva of the mosquito and migrate to the liver where it multiplies rapidly within the liver cells (hepatocytes) through a multiple asexual division, and become merozoitos entering in the bloodstream. There are still infected erythrocytes and multiply, giving rise to early forms typically annular (trophozoites), asexual division multiple ways (merotes) and finally a variable number of merozoítos depending on the species of Plasmodium, which causes the rupture of the erythrocyte. Some merozoítos become a relatively large circular cells that are male and female gametocytes and cease to multiply, but in P. falciparum are larger than the erythrocyte and boomerang-shaped, which also leads to its rupture. A female Anopheles bites an uninfected partner becomes ill and the gametocytes, and thus initiates the sexual cycle of Plasmodium. With the union of gametes in the gut, the formation of an egg, which is mobile and will give rise to a Ooquiste to re-divided and ready to sporozoites to infect again, to reach the salivary glands of the mosquito.
In humans, the clinical manifestations are due to:
The rupture of red blood cells, which release merozoitos, releasing substances that stimulate the hypothalamus, causing sudden fever crisis, very intense, every two or three days (as supplemented or asexual erythrocytic cycle of Plasmodium), followed after a few hours a sudden return to an apparently normal. This process is exhausted, leaving the body, and in the case of young children there is a high probability of a fatal outcome in the absence of treatment.
The parasite avoids the immune system by remaining intracellular in hepatocytes and erythrocytes, although many are removed parasitized erythrocytes in the spleen. To avoid this, the parasite produces proteins that are expressed on the surface of the erythrocytes and cause their adherence to vascular endothelium, particularly in Plasmodium falciparum: This is the main factor for hemorrhagic complications of malaria. These proteins are also highly variable, and therefore the immune system can not recognize them effectively, as when making a sufficient number of antibodies (at the end of two weeks or more), they will be useless because the antigen has changed.
The cycle continues when a mosquito ingests blood from a patient or carrier, and thus some gametocytes. In the gut of the mosquito become macrogametos (female) and microgametes (male), which merged to give a zygote or mobile oocineto. This eventually formed the sporozoites migrate to the mosquito salivary gland, completing the life cycle.
Pregnant women are especially attractive to mosquitoes and malaria, which is particularly harmful, given the sensitivity of the fetus (which does not have a developed immune system) to the infection.
Symptoms [edit]
It is characterized by chills, lasting from 15 minutes to an hour, beginning when a new generation of parasites and host erythrocytes breaks away into the blood. At this point it is common to have nausea, vomiting and headache. The next stage heat, which lasts several hours, accompanied by fever needle which sometimes reaches 40 ° C or more. During this phase it is possible that the parasites invade other erythrocytes. The third stage ends or sweating episode. In infections with P. vivax (benign tertiary malaria), P. Ovale or Falciparum (malaria tertiary malignant) cells are broken and there are paroxysms every 48 hours. In infections with P. Malariae (malaria quartan) cycles last for 72 hours. As the disease progresses and is less splenomegaly hepatomegaly. Infection with P. Falciparum is more important, because unlike other infections, it is most often severe or fatal complications. It is also the most difficult to identify clinically, as it often presents as an influenza-like illness with symptoms of fever, headache, myalgia, nausea, diarrhea and abdominal discomfort or pain. The fever may be fever-type, continuous or daily needles, and occur without shivering or shaking. It is sometimes difficult to identify parasites in blood smears.
Vaccine [edit]
The first to discover a synthetic vaccine against malaria was Dr. Manuel Elkin Patarroyo, of Colombian origin. Between 1986 and 1988, the synthetic vaccine (SPf66) was created and tested in a colony of monkeys in the Amazon region, the Aotus trivirgatus, and a group of young volunteers who lend their baccalaureate service. However, the problems began there, because the economic interests at stake hindered the implementation of mass vaccination.
The vaccine was tested on over 41,000 volunteers in Latin America, where in early 1994 were inoculated 45 volunteers showed that the vaccine induces a strong immune response (between 40 and 60% in adults and up to 77% children) against malaria, without causing side effects. Finally, after being evaluated in Gambia, Tanzania and Thailand, the vaccine was effective in approximately 99% of cases. This would save an estimated 1 million lives on an annual mortality rate of 3 million, making it the most effective vaccine against malaria developed until today.
Vaccines for malaria are under development, not a completely effective vaccine yet available. The first promising studies demonstrating the possibility of a malaria vaccine in 1967 were made by immunization of mice with radiation-attenuated sporozoites, providing protection to about 60% of mice after injection with normal, viable sporozoites. Since the 1970s, has been a considerable effort to develop similar vaccination strategies in humans. It was determined that a person can protect themselves from infection by P. falciparum if you receive over 1000 bites by infected mosquitoes irradación. It has been generally accepted that it is not practical to offer people at risk, this vaccination strategy, but it has been recently challenged with work being undertaken by Dr. Stephen Hoffman, heal, one of the principal investigators who originally sequence the genome of Plasmodium falciparum. His most recent work has focused on tackling the logistics of preparation and isolation of parasites equivalent to 1000 irradiated mosquitoes for mass storage and inoculation of humans. The company has recently received several multimillion-dollar grants from the Bill & Melinda Gates Foundation and the U.S. government begin in early clinical studies in 2007 and 2008. The Biomedical Research Institute Seattle (SBRI), funded by the Malaria Vaccine Initiative, said the potential volunteers that "the [2009] clinical trials will not be a life-threatening experience. While many volunteers [in Seattle ] actually get the disease, the cloned strain used in the experiments can be cured, and not cause a recurring form of the disease. "Some of the participants will get experimental drugs or vaccines, while others receive a placebo."
Instead, much work has been done to try to understand the immunological processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967 [95] is the assumption that the injected sporozoites themselves were being recognized by the immune system, which is in turn creating antibodies against the parasite. It was found that the immune system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite. [99] In addition, the antibodies against CSP prevented the sporozoite from invading hepatocytes. CSP [100], therefore, was chosen as the most promising of the protein to develop a vaccine against malaria sporozoites. For these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.
Currently, there are a variety of shots on the table. Pre-eritociticas vaccines (vaccines that target parasites before they reach the blood), in particular vaccines based on CSP, formed the largest group of research of the vaccine against malaria. Other vaccines: those that seek to induce immunity to blood stages of infection, seeking to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood venules and placenta, and transmission blocking of vaccines that stop the development of the parasite in the mosquito right after the mosquito has taken a bit of blood from an infected person. [101] It is hoped that the genome of P. falciparum will provide new targets for drugs or vaccines. [102]
Developed the first vaccine that has undergone field trials, is the SPf66, developed by Manuel Elkin Patarroyo in 1987. A combination of antigens from the sporozoite (using CS repeats) and parasites merezoite. During phase I trials of a 75% rate of effectiveness is demonstrated and the vaccine appears to be well tolerated by subjects and immunogenic. Phase IIb and III trials were less promising, with efficiency falling between 38.8% and 60.2%. One trial was conducted in Tanzania in 1993 demonstrate the effectiveness to be 31% after one year follow up, however the most recent (though controversial) study in the Gambia did not show any effect. Despite the relatively long periods of testing and the number of studies, not yet known how the SPf66 vaccine confers immunity, it remains an unlikely solution to malaria. The CSP was the next vaccine developed initially seemed enough to undergo the tests. It is also based on the circumsporozoite protein, but also has the recombinant (ASN-Pro15Asn-Ala-Val-Asp-Pro) 2-Leu-Arg (R32LR) covalently to a protein toxin purified eruginosa Nickname (A9). However at an early stage of a total lack of protection of immunity is demonstrated in the inoculated. The study group used in Kenya had an 82% incidence of parasitaemia, while the control group had only a 89% incidence. Vaccine intended to cause an increase in T cell response in those exposed, this was not observed.
The efficacy of Patarroyo vaccine has been in dispute with U.S. some scientists concluded in the journal The Lancet (1997) that "the vaccine is not effective and should be deleted, while the Colombian accused of" arrogance "to put their claims on the fact that he came from a developing country.
The RTS, S/AS02A vaccine is the candidate more, throughout the vaccine trials. Being developed by a partnership between the PATH Malaria Vaccine Initiative (a licensee of the Gates Foundation), the pharmaceutical company GlaxoSmithKline and the Walter Reed Army Institute of Research [103] in the vaccine, a part of CSP has been fused to the immunogenicity "S antigen of hepatitis B virus, and this recombinant protein is injected alongside the potent adjuvant AS02A. [101] In October 2004, the RTS, S/AS02A researchers announced the results of a Phase IIb trial, indicating the vaccine reduced infection risk by approximately 30% and the severity of infection by more than 50 %. The study examined more than 2,000 children in Mozambique. [104] A more recent trial of the RTS, S/AS02A, the vaccine has focused on the safety and effectiveness of its previous management in childhood: In October 2007, researchers announced the results of a phase I / IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three doses of the vaccine led to a 62% reduction of the infection without serious side effects except some pain at the injection site. [105] will further delay the investigation of this vaccine from commercial release until around 2011. [106]
The journal The Lancet published on October 16, 2004 the initial results of the largest clinical trial of a vaccine against malaria in Africa, in an article whose lead author is Pedro Alonso, a professor in the Department of Public Health, Faculty of Medicine University of Barcelona and head of the Unesco Chair of the Environment and Sustainable Development at the university.
Other methods [edit]
The sterile insect technique is emerging as a possible method of mosquito control. Progress towards transgenic, or genetically modified insects suggest that wild mosquito populations could become resistant to malaria. Research at Imperial College London created the first transgenic malaria mosquito, [107] with the first resistant Plasmodium species announced by a team from Case Western Reserve University in Ohio in 2002. [108] The success of the replacement of existing populations with genetically modified populations, relies on a transmission mechanism, such as transposable elements to allow for Mendelian inheritance of genes of interest.
Education in recognizing the symptoms of malaria has reduced the number of cases in some areas of the developing world as much as 20%. Recognize the disease in early stages can also stop the disease from becoming a murderer. Education can also inform people to cover more areas of stagnant, for example, the water still water tanks, which are ideal breeding grounds for the parasite and the mosquito, thus reducing the risk of transmission between people. It is put into practice in most urban areas with large population centers in a space and transmission would be most likely in these areas.
On December 22, 2007, publication PLoS Pathogens study found that sea cucumbers are blocking the transmission of the malaria parasite, which produce the protein, lecithin (which slows the growth of parasites). [109]
Before DDT, malaria had been eradicated or controlled in several tropical areas by removing or poisoning the breeding of mosquitoes or the aquatic habitats of the larva stages, for example, or the application of oil-filled to places with standing water. These methods have seen little application in Africa for more than half a century. [110]
Another way to tackle malaria in the Third World that has been used extensively in the past to combat the vector of transmission is the use of insecticides such as pyrethrins or DDT. It banned the use of the latter because of their potential effects on health and wildlife, but a group of scientists believes that this prohibition should be reviewed so strict. [18] It has a measured use for medical purposes, other than the use for economic mass that was in the past, is a good option for control or eradication of malaria under highly controlled, limited to the interior of the houses and roofs in areas where malaria is endemic, according to WHO. Some environmental groups such as the Pesticide Action Network does not agree with this measure. [19
Wednesday, March 25, 2009
Malaria
Malaria or malaria is a parasitic disease that is transmitted from human to human by the bite of infected Anopheles mosquitoes. In humans, the parasites (called sporozoites) migrate to the liver where they mature and become merozoítos, which enter the bloodstream and infect red blood cells.
The parasites multiply within cells that, after 48 to 72 hours, breaks and infect more red blood cells. The first symptoms are usually from 10 days to 4 weeks after infection, but sometimes can occur in a span of 8 days to 1 year later. Then the symptoms occur in cycles of 48 to 72 hours.
Most symptoms are caused by the massive release of merozoítos in the bloodstream, the anemia caused by destruction of red blood cells and problems due to large amounts of free hemoglobin that invade the bloodstream after the rupture of blood cells red.
The transmission of malaria may also be a congenital (from mother to fetus) and blood transfusions. Malaria is transmitted through the mosquito in temperate zones, but the parasite disappears when winter comes.
This disease is a greater health problem in most tropical and subtropical countries. The CDC (Center for Disease Control in the U.S.) estimates that each year are from 300 to 500 million cases of malaria and over one million are fatal. Is the disease of greatest risk for people who move to warmer climates.
In some regions of the world, the mosquito that transmits malaria has developed resistance to insecticides substances, while the parasite has developed resistance to antibiotics. This has led to difficulty in controlling the rate of infection and the spread of the disease.
Of the four species of parasites exist, Falciparum malaria caused by destroying a greater proportion of red blood cells in comparison with other species and is considered a much more serious disease. It can be fatal to the early hours of onset of first symptoms.
> tukar
The parasites multiply within cells that, after 48 to 72 hours, breaks and infect more red blood cells. The first symptoms are usually from 10 days to 4 weeks after infection, but sometimes can occur in a span of 8 days to 1 year later. Then the symptoms occur in cycles of 48 to 72 hours.
Most symptoms are caused by the massive release of merozoítos in the bloodstream, the anemia caused by destruction of red blood cells and problems due to large amounts of free hemoglobin that invade the bloodstream after the rupture of blood cells red.
The transmission of malaria may also be a congenital (from mother to fetus) and blood transfusions. Malaria is transmitted through the mosquito in temperate zones, but the parasite disappears when winter comes.
This disease is a greater health problem in most tropical and subtropical countries. The CDC (Center for Disease Control in the U.S.) estimates that each year are from 300 to 500 million cases of malaria and over one million are fatal. Is the disease of greatest risk for people who move to warmer climates.
In some regions of the world, the mosquito that transmits malaria has developed resistance to insecticides substances, while the parasite has developed resistance to antibiotics. This has led to difficulty in controlling the rate of infection and the spread of the disease.
Of the four species of parasites exist, Falciparum malaria caused by destroying a greater proportion of red blood cells in comparison with other species and is considered a much more serious disease. It can be fatal to the early hours of onset of first symptoms.
> tukar
Monday, March 23, 2009
Diabetes And Joint Disease
Introduction
Diabetes mellitus that characterized by chronic hyperglycemia which is accompanied by protein and lipid metabolic disorders could affect the bone and joint in a variety of ways. It is not surprisingly that the complex metabolic disturbances in diabetes cause a wide range of alteration in the musculo-skeletal system. For example, diabetes could play a role in osteoporosis, hyperostosis such as DISH or diffuse idiopathic skeletal hyperostosis (particularly in type II diabetes), osteoarthritis, diabetic osteoarthropathy, diabetic hand syndrome, rheumatoid arthritis and shoulder calcific periarthritis.
These conditions mentioned above appear not only as independent disease (e.g. diabetic osteoarthropathy), but also as modifications in frequency and course of various rheumatic processes. Several rheumatic condition in diabetes mellitus will be discussed in this paper except osteoporosis.
Diabetes and Hyperostosis
The association of diabetes and hyperostosis was recognized as early as 1954. The radiological appearance noted that the changes could be differentiated from spondylosis deformans and ankylosing spondylitis.
The pathology of hyperostosis is essentially metaplastic calcification and ossification of the anterior longitudinal ligaments of the spine. This calcification almost accompanied by generalized ossification of ligaments and tendons. Resnick et al summarized these changes under the name diffuse idiopathic skeletal hyperostosis (DISH).
In diabetic patient the frequency of hyperostosis is markedly increased compared to normal population. It occurs in diabetics and normal population in 13-49% and 1.6-13% respectively. Almost three times of the diabetic patient with hyperostosis had type II diabetes rather than type I. Although hyperostotic process develops earlier in diabetics, DISH is a disease of the elderly which frequently increases with age.
The relationship between diabetes and hyperostosis is not clearly understood. It has already proven that insulin or insulin-like growth factors-1 (IGF-1) at prolonged and high level promotes bone formation particularly in the entheseal region. This explanation perhaps could answer why hyperostosis most common seen in type II diabetes due to prolonged hyperinsulinemia. Furthermore this changes is nearly three times more frequent among diabetic patient with hyperlipoproteinemia. In post menopausal women commonly seen an overproduction of growth hormone and hyperostosis have features in common with acromegaly. It is difficult to answer the question weather hyperostosis is a diabetic feature. So do the overproduction of growth hormone in postmenopausal women in relationship with hyperostosis. DISH is not specific diabetic complication and hyperostosis is not a direct consequence of diabetes.
Diabetes and Osteoarthritis
One of the most common rheumatologic diseases is osteoarthritis (OA) in correlation with or without diabetes. It is distributed in all part of the world with the frequency less than 5% below 45 years of age and sharply increased in the sixth, seventh and eight decade. The radiological change is much higher than clinical manifestation giving up to 83%. In one study of OA in Malang, Indonesia, the prevalence in urban and rural area is 10.0% and 13.5% respectively, while in USA as reported by Altman, the OA prevalence is 12% among total population.
This rheumatic alteration seems more frequent in type II diabetes. In type II diabetes the disease is insulin resistant, due to insulin receptor and postreceptor abnormalities. Insulin itself known as a potent growth factor for connective tissue. Horn et al conducted a study on radiographic features from 25 diabetic patients with OA compare to those without diabetes and the result suggested that diminished availability of insulin at the cellular level or diabetic microvascular disease attenuates the chondro- and osteogenesis required for osteophyte formation in the joints of patients with OA.
There is lack of specific explanation regarding the correlation between diabetes and OA. Since the diabetic patients are obese and it is well known that obesity is one of risk factor for OA independent of diabetes, so the connection is more likely due to obesity rather than diabetes itself. Obesity in women is known cause of hyperoestrogenism, occurring through the peripheral formation of estrogen from androstenedione in fat tissues. After the menopause this route becomes the principal source of estrogen. It is understandable that OA and obesity also suggest a role for endocrine influences in the development of OA. An unanswered question is which pathogenic pathway obesity causes OA.
Weight bearing joint such as knee joint is the most affected joint. Kalim reported that knee OA is much higher seen in diabetics with good metabolic controlled and those with high estradiol and insulin level. Duration of diabetes and poor metabolic controlled diabetes increases the risk for having symptomatic OA. His study failed to support the role of IGF-1 and growth hormone as other factors in the occurrence of OA. As we know that IGF-1 could stimulate the synthesis of proteoglycan, one of the essential structure in the cartilage matrix. In diabetics, IGF-1 level had significantly lower than normal subject up to 50% as mentioned by Tan and Baxter did.
There are no significant differences in the management of OA in diabetic patient. It is advisable to bring the patient’s body weight down to normal or ideal body weight since Felson et al analysis the data from Framingham OA study and was founded that weight loss reduces the risk for symptomatic knee OA in women. The need of hyperglycemic controlled; various modalities in physiotherapy including joint protection and the use of medication particularly painkiller, non-steroidal anti inflammatory drugs or other nutraceutical agents such as chondroitin sulfate, and glucosamine sulfate is mandatory. Unfortunately there is no drugs acting on chondrocyte function as disease modifying anti osteoarthritic drugs. Attention must be given to those with hormone replacement therapy even though that estrogen use in women is not associated with increased risk of radiographic OA. In theory estrogen will bring the subchondral bone relatively stiffer and it cause a higher transmission of impulse loading force to the overlying cartilage leading to cartilage damage. This will initiating the cartilage changes as the main abnormalities in OA.
Diabetic Osteoarthropathy
This terminology applies to destructive lytic bone changes mainly in the pedal bones and it is a severe late complication of diabetes. The changes more frequently seen among the 50- to 69-year-old patients with no sex differences in sex distribution.
Metatarsophalangeal (31.5%) joint is the most affected site in diabetic osteoarthropathy, followed by tarsometatarsal joint (27.4%), tarsus (21.8%), ankle joint (10.2%) and interphalangeal joints (9.1%). The bone abnormality increases with the duration of diabetes. The duration of diabetes more than 10 years giving more than half the incidence of diabetic osteoarthropathy.
Neuropathy plays the important role in the development of diabetic osteoarthropathy beside some other factors aggravating the pathologic process such as infection, vasculopathy (diabetic micro- and macro-angiopathy) and joint trauma.
The clinical symptoms are not related with the severity of radiological findings, so it is often revealed after severe irreversible bone changes have developed. The clinical manifestation can be divided in four groups as neurological symptoms appear the first and then the skin involvement developed, subsequently followed by loosening of joints and articular swelling and those leading to joint deformities.
The x-ray examination is the instrument to make the diagnosis of diabetic osteoarthropathy and there are three characteristic changes. The first radiological change is the appearance of circumscribed osteoporosis, mostly at the subchondral region and gradually turn into osteolysis. At this initial stage other abnormalities such as cortical defect and subluxation or dislocation can be demonstrated. The second stage or progression stage will give further severe osteolysis, fragmentation, fractures and periosteal reaction. The last stage, namely the healing stage, it is not pointed to the recovery of the pathologic process but more likely the end stage or deforming one. At this stage the filling process of cortical defect resulting in pointed bones, development of arthrosis deformans, ankylosis and total restitution.
It is advisable to differentiate between diabetic osteoarthropathy with inflammatory, tumorous, degenerative processes and of neurogenic arthrophaties origin.
The clinical management referred to the controlled of pathogenic factors. Conservative treatment is indicated in most cases. Remember that neuropathy is the dominating factor. It is advisable to maintain the good metabolic controlled, which is often mean to use insulin rather than oral hypoglycemic agents. Other important thing is joint protection from weight bearing and the use of orthotic device is much of help. Amputation and resection is justifiable in cases with severe infection (macroangiopathy or gangrenous) or in cases of nonhealing plantar ulcer particularly for the maintenance of remission after recovery. Usually this was limited to removal of destroyed capitulum or the base of the phalanx. The fundamental consideration in preventing diabetic osteoarthropathy is good diabetic controlled and foot hygiene.
Diabetes and Rheumatoid Arthritis
There is some similarities on several factors that plays a role in the disease process that can be seen in diabetic (type I) and rheumatoid arthritic (RA) patient. These factors detected in similar frequency between the two, such as HLA-DR3 and / or DR4, decreases in C4 level, islet cell antibodies and other systemic and organ specific antibodies. Although other study conducted by Pile demonstrated that interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune disease, but in type I diabetes the susceptibility to have RA enhances (RR=5-6) in the present of HLA DR4. It is still debatable how the pathologic process of RA is modified by concomitant diabetes. Thomas et al mentioned for the first time that there is increase in prevalence of type 1 diabetes in the close relatives of patients with RA. They founded that 13% of 295 patients satisfy the classical RA had a first or second degree relative with type I diabetes and of 13% had a close relative with autoimmune thyroid disease. Cornelis F et al, in their genome study demonstrated that there is no other locus than HLA giving similarity between RA and types I diabetes mellitus.
Diabetes and Shoulder Problems.
Commonly the shoulder problem in type II diabetes is calcific periarthritis or tendinitis. Mavrikakis et al had founded that 31.8 % of 824 diabetics had shoulder calcification in compared with 10.3% of 320 non-diabetics. The calcific periarthritis occurs in younger patients and the sites of calcification most common on the right shoulder particularly lies within the supra spinatus tendon. Calcification influenced by the factor of long duration of having diabetes particularly those treated with insulin for a long time.
The deposition of calcium-containing crystal around joint will appear radiologically as diffuse or small dense opacities. This appearance is not significantly related with clinical manifestation. In acute periarthritis which can be so painful that examination of the shoulder become impossible. This occurs when the calcium containing material penetrate into the neighboring bursa and the crystal induce an acute synovitis.
The management is symptomatic and at the acute stage draining the chalk-like material is much of help. If not drained, the calcific material is resorbed and dissapears from the radiograph.
Diabetic Hand Syndrome
In diabetics limited joint mobility was associated with several factors including microangiopathy and collagen changes. It is not clear yet weather microangiopathy occurs first with several complication such as ischemia and fibrosis of the connective tissue or the collagen changes cause small vessel disease. It occurs in 8-50% of type I diabetics. The symptoms developed after a long duration of diabetic metabolic disturbances. Most of the cases started in childhood. Clarke CF et al founded that 31% of 70 diabetic children have limited joint mobility and the prevalence increases with age and duration of diabetes.
Clinically, slight pain and paresthesias developed first and then the pain will aggravated by hand movement. The patient is unable to press both hands together.
There is no specific management for these abnormalities, but the main task is to maintain the diabetic control and perhaps the use of periphery vasodilator and symptomatic treatment are recommended.
References
1. Thomas DJ, Young A, Gorsuch AN, Bottazo GF, Cudworth AG. Evidence for an association between rheumatoid arthritis and endocrine disease. Ann Rheum Dis 1983; 42:297-300.
2. Mavrikakis ME, Drimis S, Kontoyannis DA, Rasidakis A, Moulopoulou ES, Kontoyannis S. Calcific shoulder periarthritis (tendinitis) in adult onset diabetes mellitus: a controlled study. Ann Rheum Dis 1989; 48:211-4.
3. Vischer TL. Non-articular rheumatism. In Dieppe PA, Bacon PA, Bamji AN, Watt I. Atlas of clinical rheumatology. London: Gower Medical Publishing 1986: 20.20 2
4. Forgacs SS. Endocrine and hemoglobin arthropathies. In Klippel ed. Textbook of Rheumatology. …… 7.20.1 – 6.
5. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JA. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Intern Med 1992; 116:535-9.
6. Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: The Chingford study. J Rheumatol 1993;20:331-5.
7. Felson DT, Anderson DJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. Ann Intern Med. 1988;109:18-24.
8. Cornelis F, Faure S, Martinez M, et al. New susceptibility locus for rheumjatoid arthritis sugessted by genom-wide linkage study. PNAS 1998;95:10746-50.
9. Kawahito Y, Cannon GW, Gulko PS, et al. Localization of quantitative trait loci regulating adjuvant-induced arthritis in rats: Evidence of genetic factors common to multiple autoimmune disease. J Immunol 1998;161: 4411-9
10. Hannan MT, Felson DT, Anderson DJ, Naimark A, Kannel WB. Estrogen use and radiographic osteoarthritis of the knee in women. Arthritis Rheum 1990;33: 525-32
11. Pile KD, Wordsworth BP, Bell JI. Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?. Ann Rheum Dis 1992;51:1250-1
12. Horn CA, Bradley JD, Brandt KD, et al. Impairment of osteophyte formation in hyperglycemic patients with type II diabetes mellitus and knee osteoarthritis. Arthritis Rheum 1992;35:336-42
13. Tan K, Baxter RC. Serum insulin-like growth factor I level in adfult diabetic patients: The effect of age. J Clin Endocrinol Metab 1986;63:651-5
14. Hartz AJ, Fischer ME, Bril G, et al. The association of obesity with joint pain and osteoarthritis in the HANES data. J Chron Dis 1986;39:311-9.
15. Spector TD, Campion GD. Generalized osteoarthritis: a hormonally mediated disease. Ann Rheum Dis 1989;523-7
16. Chander CL, Spector TD. Oestrogen, joint disease and cartilage. Ann Rheum Dis 1991;50:139-40.
Diabetes mellitus that characterized by chronic hyperglycemia which is accompanied by protein and lipid metabolic disorders could affect the bone and joint in a variety of ways. It is not surprisingly that the complex metabolic disturbances in diabetes cause a wide range of alteration in the musculo-skeletal system. For example, diabetes could play a role in osteoporosis, hyperostosis such as DISH or diffuse idiopathic skeletal hyperostosis (particularly in type II diabetes), osteoarthritis, diabetic osteoarthropathy, diabetic hand syndrome, rheumatoid arthritis and shoulder calcific periarthritis.
These conditions mentioned above appear not only as independent disease (e.g. diabetic osteoarthropathy), but also as modifications in frequency and course of various rheumatic processes. Several rheumatic condition in diabetes mellitus will be discussed in this paper except osteoporosis.
Diabetes and Hyperostosis
The association of diabetes and hyperostosis was recognized as early as 1954. The radiological appearance noted that the changes could be differentiated from spondylosis deformans and ankylosing spondylitis.
The pathology of hyperostosis is essentially metaplastic calcification and ossification of the anterior longitudinal ligaments of the spine. This calcification almost accompanied by generalized ossification of ligaments and tendons. Resnick et al summarized these changes under the name diffuse idiopathic skeletal hyperostosis (DISH).
In diabetic patient the frequency of hyperostosis is markedly increased compared to normal population. It occurs in diabetics and normal population in 13-49% and 1.6-13% respectively. Almost three times of the diabetic patient with hyperostosis had type II diabetes rather than type I. Although hyperostotic process develops earlier in diabetics, DISH is a disease of the elderly which frequently increases with age.
The relationship between diabetes and hyperostosis is not clearly understood. It has already proven that insulin or insulin-like growth factors-1 (IGF-1) at prolonged and high level promotes bone formation particularly in the entheseal region. This explanation perhaps could answer why hyperostosis most common seen in type II diabetes due to prolonged hyperinsulinemia. Furthermore this changes is nearly three times more frequent among diabetic patient with hyperlipoproteinemia. In post menopausal women commonly seen an overproduction of growth hormone and hyperostosis have features in common with acromegaly. It is difficult to answer the question weather hyperostosis is a diabetic feature. So do the overproduction of growth hormone in postmenopausal women in relationship with hyperostosis. DISH is not specific diabetic complication and hyperostosis is not a direct consequence of diabetes.
Diabetes and Osteoarthritis
One of the most common rheumatologic diseases is osteoarthritis (OA) in correlation with or without diabetes. It is distributed in all part of the world with the frequency less than 5% below 45 years of age and sharply increased in the sixth, seventh and eight decade. The radiological change is much higher than clinical manifestation giving up to 83%. In one study of OA in Malang, Indonesia, the prevalence in urban and rural area is 10.0% and 13.5% respectively, while in USA as reported by Altman, the OA prevalence is 12% among total population.
This rheumatic alteration seems more frequent in type II diabetes. In type II diabetes the disease is insulin resistant, due to insulin receptor and postreceptor abnormalities. Insulin itself known as a potent growth factor for connective tissue. Horn et al conducted a study on radiographic features from 25 diabetic patients with OA compare to those without diabetes and the result suggested that diminished availability of insulin at the cellular level or diabetic microvascular disease attenuates the chondro- and osteogenesis required for osteophyte formation in the joints of patients with OA.
There is lack of specific explanation regarding the correlation between diabetes and OA. Since the diabetic patients are obese and it is well known that obesity is one of risk factor for OA independent of diabetes, so the connection is more likely due to obesity rather than diabetes itself. Obesity in women is known cause of hyperoestrogenism, occurring through the peripheral formation of estrogen from androstenedione in fat tissues. After the menopause this route becomes the principal source of estrogen. It is understandable that OA and obesity also suggest a role for endocrine influences in the development of OA. An unanswered question is which pathogenic pathway obesity causes OA.
Weight bearing joint such as knee joint is the most affected joint. Kalim reported that knee OA is much higher seen in diabetics with good metabolic controlled and those with high estradiol and insulin level. Duration of diabetes and poor metabolic controlled diabetes increases the risk for having symptomatic OA. His study failed to support the role of IGF-1 and growth hormone as other factors in the occurrence of OA. As we know that IGF-1 could stimulate the synthesis of proteoglycan, one of the essential structure in the cartilage matrix. In diabetics, IGF-1 level had significantly lower than normal subject up to 50% as mentioned by Tan and Baxter did.
There are no significant differences in the management of OA in diabetic patient. It is advisable to bring the patient’s body weight down to normal or ideal body weight since Felson et al analysis the data from Framingham OA study and was founded that weight loss reduces the risk for symptomatic knee OA in women. The need of hyperglycemic controlled; various modalities in physiotherapy including joint protection and the use of medication particularly painkiller, non-steroidal anti inflammatory drugs or other nutraceutical agents such as chondroitin sulfate, and glucosamine sulfate is mandatory. Unfortunately there is no drugs acting on chondrocyte function as disease modifying anti osteoarthritic drugs. Attention must be given to those with hormone replacement therapy even though that estrogen use in women is not associated with increased risk of radiographic OA. In theory estrogen will bring the subchondral bone relatively stiffer and it cause a higher transmission of impulse loading force to the overlying cartilage leading to cartilage damage. This will initiating the cartilage changes as the main abnormalities in OA.
Diabetic Osteoarthropathy
This terminology applies to destructive lytic bone changes mainly in the pedal bones and it is a severe late complication of diabetes. The changes more frequently seen among the 50- to 69-year-old patients with no sex differences in sex distribution.
Metatarsophalangeal (31.5%) joint is the most affected site in diabetic osteoarthropathy, followed by tarsometatarsal joint (27.4%), tarsus (21.8%), ankle joint (10.2%) and interphalangeal joints (9.1%). The bone abnormality increases with the duration of diabetes. The duration of diabetes more than 10 years giving more than half the incidence of diabetic osteoarthropathy.
Neuropathy plays the important role in the development of diabetic osteoarthropathy beside some other factors aggravating the pathologic process such as infection, vasculopathy (diabetic micro- and macro-angiopathy) and joint trauma.
The clinical symptoms are not related with the severity of radiological findings, so it is often revealed after severe irreversible bone changes have developed. The clinical manifestation can be divided in four groups as neurological symptoms appear the first and then the skin involvement developed, subsequently followed by loosening of joints and articular swelling and those leading to joint deformities.
The x-ray examination is the instrument to make the diagnosis of diabetic osteoarthropathy and there are three characteristic changes. The first radiological change is the appearance of circumscribed osteoporosis, mostly at the subchondral region and gradually turn into osteolysis. At this initial stage other abnormalities such as cortical defect and subluxation or dislocation can be demonstrated. The second stage or progression stage will give further severe osteolysis, fragmentation, fractures and periosteal reaction. The last stage, namely the healing stage, it is not pointed to the recovery of the pathologic process but more likely the end stage or deforming one. At this stage the filling process of cortical defect resulting in pointed bones, development of arthrosis deformans, ankylosis and total restitution.
It is advisable to differentiate between diabetic osteoarthropathy with inflammatory, tumorous, degenerative processes and of neurogenic arthrophaties origin.
The clinical management referred to the controlled of pathogenic factors. Conservative treatment is indicated in most cases. Remember that neuropathy is the dominating factor. It is advisable to maintain the good metabolic controlled, which is often mean to use insulin rather than oral hypoglycemic agents. Other important thing is joint protection from weight bearing and the use of orthotic device is much of help. Amputation and resection is justifiable in cases with severe infection (macroangiopathy or gangrenous) or in cases of nonhealing plantar ulcer particularly for the maintenance of remission after recovery. Usually this was limited to removal of destroyed capitulum or the base of the phalanx. The fundamental consideration in preventing diabetic osteoarthropathy is good diabetic controlled and foot hygiene.
Diabetes and Rheumatoid Arthritis
There is some similarities on several factors that plays a role in the disease process that can be seen in diabetic (type I) and rheumatoid arthritic (RA) patient. These factors detected in similar frequency between the two, such as HLA-DR3 and / or DR4, decreases in C4 level, islet cell antibodies and other systemic and organ specific antibodies. Although other study conducted by Pile demonstrated that interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune disease, but in type I diabetes the susceptibility to have RA enhances (RR=5-6) in the present of HLA DR4. It is still debatable how the pathologic process of RA is modified by concomitant diabetes. Thomas et al mentioned for the first time that there is increase in prevalence of type 1 diabetes in the close relatives of patients with RA. They founded that 13% of 295 patients satisfy the classical RA had a first or second degree relative with type I diabetes and of 13% had a close relative with autoimmune thyroid disease. Cornelis F et al, in their genome study demonstrated that there is no other locus than HLA giving similarity between RA and types I diabetes mellitus.
Diabetes and Shoulder Problems.
Commonly the shoulder problem in type II diabetes is calcific periarthritis or tendinitis. Mavrikakis et al had founded that 31.8 % of 824 diabetics had shoulder calcification in compared with 10.3% of 320 non-diabetics. The calcific periarthritis occurs in younger patients and the sites of calcification most common on the right shoulder particularly lies within the supra spinatus tendon. Calcification influenced by the factor of long duration of having diabetes particularly those treated with insulin for a long time.
The deposition of calcium-containing crystal around joint will appear radiologically as diffuse or small dense opacities. This appearance is not significantly related with clinical manifestation. In acute periarthritis which can be so painful that examination of the shoulder become impossible. This occurs when the calcium containing material penetrate into the neighboring bursa and the crystal induce an acute synovitis.
The management is symptomatic and at the acute stage draining the chalk-like material is much of help. If not drained, the calcific material is resorbed and dissapears from the radiograph.
Diabetic Hand Syndrome
In diabetics limited joint mobility was associated with several factors including microangiopathy and collagen changes. It is not clear yet weather microangiopathy occurs first with several complication such as ischemia and fibrosis of the connective tissue or the collagen changes cause small vessel disease. It occurs in 8-50% of type I diabetics. The symptoms developed after a long duration of diabetic metabolic disturbances. Most of the cases started in childhood. Clarke CF et al founded that 31% of 70 diabetic children have limited joint mobility and the prevalence increases with age and duration of diabetes.
Clinically, slight pain and paresthesias developed first and then the pain will aggravated by hand movement. The patient is unable to press both hands together.
There is no specific management for these abnormalities, but the main task is to maintain the diabetic control and perhaps the use of periphery vasodilator and symptomatic treatment are recommended.
References
1. Thomas DJ, Young A, Gorsuch AN, Bottazo GF, Cudworth AG. Evidence for an association between rheumatoid arthritis and endocrine disease. Ann Rheum Dis 1983; 42:297-300.
2. Mavrikakis ME, Drimis S, Kontoyannis DA, Rasidakis A, Moulopoulou ES, Kontoyannis S. Calcific shoulder periarthritis (tendinitis) in adult onset diabetes mellitus: a controlled study. Ann Rheum Dis 1989; 48:211-4.
3. Vischer TL. Non-articular rheumatism. In Dieppe PA, Bacon PA, Bamji AN, Watt I. Atlas of clinical rheumatology. London: Gower Medical Publishing 1986: 20.20 2
4. Forgacs SS. Endocrine and hemoglobin arthropathies. In Klippel ed. Textbook of Rheumatology. …… 7.20.1 – 6.
5. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JA. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Intern Med 1992; 116:535-9.
6. Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: The Chingford study. J Rheumatol 1993;20:331-5.
7. Felson DT, Anderson DJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. Ann Intern Med. 1988;109:18-24.
8. Cornelis F, Faure S, Martinez M, et al. New susceptibility locus for rheumjatoid arthritis sugessted by genom-wide linkage study. PNAS 1998;95:10746-50.
9. Kawahito Y, Cannon GW, Gulko PS, et al. Localization of quantitative trait loci regulating adjuvant-induced arthritis in rats: Evidence of genetic factors common to multiple autoimmune disease. J Immunol 1998;161: 4411-9
10. Hannan MT, Felson DT, Anderson DJ, Naimark A, Kannel WB. Estrogen use and radiographic osteoarthritis of the knee in women. Arthritis Rheum 1990;33: 525-32
11. Pile KD, Wordsworth BP, Bell JI. Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?. Ann Rheum Dis 1992;51:1250-1
12. Horn CA, Bradley JD, Brandt KD, et al. Impairment of osteophyte formation in hyperglycemic patients with type II diabetes mellitus and knee osteoarthritis. Arthritis Rheum 1992;35:336-42
13. Tan K, Baxter RC. Serum insulin-like growth factor I level in adfult diabetic patients: The effect of age. J Clin Endocrinol Metab 1986;63:651-5
14. Hartz AJ, Fischer ME, Bril G, et al. The association of obesity with joint pain and osteoarthritis in the HANES data. J Chron Dis 1986;39:311-9.
15. Spector TD, Campion GD. Generalized osteoarthritis: a hormonally mediated disease. Ann Rheum Dis 1989;523-7
16. Chander CL, Spector TD. Oestrogen, joint disease and cartilage. Ann Rheum Dis 1991;50:139-40.
Osteoarthritis and its Management
Osteoarthritis (OA) is a clinical spectrum ranging from localized chondral defects to established arthrosis resulting from hyaline cartilage failure. OA is the most common rheumatic disease found in the population. It is estimated the prevalence around 12% in the total population (USA) and about 10.0% (urban) – 13.5% (rural) in Malang, East Java, Indonesia. The radiological OA is estimated much higher (85%) compared to the clinical OA in the population by the age of 65 years. OA is characterized by progressive degradation of the components of the extra-cellular matrix (ECM) of the articular cartilage, associated with secondary inflammatory factors. The specific etiological factor is unknown, but many factors play a role in the destruction process or remodeling system. It depends on the joint involved and the factors recognized that OA would be primary or secondary. Clinically OA characterized by gradual development of joint pain, stiffness, limitation of movement and swelling. The treatment strategy comprised of two different modalities that are non-pharmacological treatment and pharmacological treatment, including surgery. The treatment depends on the patient’s age, the severity of arthrosis and physical expectations. The important things in the group of non-pharmacological approach other than weight reduction program and lifestyle changes are medical rehabilitation program, i.e. the use of assisted devices, braces and footwear modification. Non-steroidal anti-inflammatory drugs (NSAIDs) and other painkillers were the most prescribed drugs. There is some consideration in choosing of NSAIDs, including the efficacy, patient tolerance, safety, cost, drug interaction etc. Amongst them, Meloxicam is one of NSAIDs regularly used in treating OA. Some clinical trial such as MELISSA, SELECT, IMPROVED, NICE etc are looking for the efficacy, tolerability, safety profile of Meloxicam.
Sunday, March 22, 2009
Gouty Arthritis : History and Development in Asian Regions
There are few studies of crystal arthropathy, although there have been many reports of cases of gout in Asia. Like other parts of the world, gout in Asian countries is frequently found in middle aged men and may lead to deformities and disabilities.
EPIDEMIOLOGY
The prevalence of gout varies from one population to another and within populations between geographical areas. Any assessment of the incidence of gout in any population group will depend upon the criteria used to establish the diagnosis. Previous reports revealed that the incidence of hyperuricemia and gout is higher in a number of Asian races living in the USA than in comparable groups living in their homeland.1 For instance the rate of hyperuricemia and gout among the Filipinos living in Hongkong or in United States is significantly higher than those living in their native countries.1, 2
There is evidence that the distribution of serum uric acid (SUA) has changed, more people are now showing higher SUA levels with subsequent increased risk for gout.3 The three ethnic groups in Malaysia, the Malay (Malayo-Polynesians), Tamils and Chinese (Mongoloid) showed higher mean SUA levels compared with most Caucasian populations. This suggests that the influence of environmental factors might be of significance.4
The WHO-ILAR-COPCORD stage I phase 3 research in Bandungan, central Java, Indonesia, showed that the frequency of hyperuricemia and gout in males 15 years of age and over is high compared with Caucasian population. This is despite a lower life expectancy, low social class, and abstinence of alcohol and subsistence economy. The prevalence of gout was 0.8% in the 4.683 people 15 years and older. The overall male to female ratio was thirty-four to one. Gout occurred in 1.7% of the men and 0.05% of the women. It was predominantly found in men over 45 years. Acute gouty arthritis and chronic tophaceous gout were both found in this population sample.5
In Taiwan, it was found that the incidence of gout in rural and urban area were 13.6/1,000 and 6.4/1,000 respectively while the prevalence of gout were 0.6% (rural) and 0.67% (urban).6 In the clinical study of 45 gout patients in Ujung Pandang (South Sulawesi, Indonesia) the rate of hyperuricemia was 88.0%7 while in North Sulawesi, it was found that among the 208 chronic gout patients, 92.3% had hyperuricemia8. The occurrence of gout was frequent in the patients' family in North Sulawesi.
CLINICAL FEATURES AND COMPLICATIONS
In several Asian countries, the clinical features of gout seem to be different from Western countries. In the northern part of Thailand it was found that of 75 patients analyzed, the mean age was 58 years. The mean duration of disease was 6.7 years. Ankles were the most common sites of attack (45%) followed by first metatarsophalangeal joint (28%) and knee (24%). Tophi were present in 47% with the mean disease duration before onset of tophi was 5.6 years. Fifty five percent had impaired renal function (creatinine > 1.5 mg/dl). Urinary stones were found in 33%, hypertension in 56% and diabetes mellitus in 7% of patients.9 The study of gouty arthritis and uric acid levels in several ethnic groups in Ujung Pandang, South Sulawesi, Indonesia suggest that in Indonesia gout is a common and severe arthritic condition for which patients often present too late for effective treatment. More than 50% of patients with tophi have noted these for 7 – 9 years before coming for their first treatment. Tophaceous gout was not clearly associated with any one ethnic group.7
A study of 190 chronic tophaceous gout patients in North Sulawesi, Indonesia, showed that about 32.2% of patients experienced their first attack of gout when they were less than 34 years old. Multiple tophi and deformities were found in 80% of cases, they had tophi for 5 – 10 years, and kidney stones were found in 12% of cases.
In University Santo Thomas Hospital, Philippines, a study found 6 males developing gout before age 20, 44 patients between 20 - 29 years of age, and another subgroup of 124 males. With disease onset between 30 – 39 years. The youngest male patient was 12 years old. These patients was characterized by an earlier onset of gouty arthritis, with an average age of 20 years, leading to more severe joint involvement and tophaceous deposition, more severe renal damage with kidney stone formation. Uncommon clinical presentation of gout were found in this country, such as those involving pre-menopausal women, early onset in males polyarticular gout, the occurrence of gout with systemic lupus erythematosus and rheumatoid arthritis and some unusual sites of urate deposition.10
In Malaysian study, the clinical features of gout were similar to other Asian countries. Renal stones and positive family history were noticed in 42% and 30% respectively.11 A retrospective study in Alexandria hospital, Singapore, disclosed that 66% of cases (n: 51) were obese with body mass index >25. The commonest joint involvement was MTP I (51%), knees (49%), and ankles (46%). Tophi were noticed in 31% of cases.12
TREATMENT
The COPCORD survey in Indonesia indicated that more than 60% of rheumatic patients had sought help from the rural or urban primary health centers (PHCs), general practitioner, or nurses or primary health care workers. It was also found that 74% of the urban and 71% of the rural population with rheumatism resorted to self medication by buying “over the counter” tablets and capsules. These drugs were found to be prescription drugs containing glucocorticoid or phenylbutazone or a mixture of both. With their spectacular short-term therapeutic relief of joint inflammation and pain these agents are apt to increase in popularity 5. Thiazid diuretics (HCT) are widely used in community health centers in Indonesia.
A study in South Sulawesi revealed that patients first come for treatment after an average of 6.6 years following the first attack of gout.7 A survey in North Sulawesi found that there were no urate lowering drugs available in PHCs in this area. Most patients had never received any adequate treatment for gout.8
CONCLUSION
Based on several studies in some Asia countries, it was found that clinical features of gout seem to be different from Western countries. Gout patients seen in the Philippines and Northern Sulawesi (Indonesia) and northern part of Thailand were younger than other countries.
The duration of gout in Thailand and South Sulawesi (Indonesia) are similar. Overweight was found in the study Singapore and North Sulawesi (Indonesia), however in Thailand, most of gout patients were underweight and malnourished. First attack of gout in most Asian countries such as Indonesia, Singapore was at the first metatarsophalangeal, however in Thailand, the ankle was the most frequently affected joint. Tophi were found in most countries such as Indonesia, Singapore, and Thailand. Hypertension and kidney involvement was reported as the frequent complication in these areas.
Thiazide diuretics were used in the PHCs to treat high blood pressure and were suspected as a risk factor for gout. There was no report from other Asian countries regarding the treatment of gout in their countries.
Further studies are needed to clarify the differences of pattern of gout from one country to another.
REFERENCES
1. Emmerson B.T. Incidence of Gout in Different Populations. Hyperuricemia and Gout in Clinical Practice, 1983:70.
2. Zimmet P.Z, Whitehouse S, Jackson L, Thoma K. High Prevalence of Hyperuricemia and Gout in an Urbanized Micronesian Population. Br Med J 1878;1:1237-9.
3. Roubenoff R. Incidence and Prevalence of Gouty arthritis. Rheum Dis Clin of North America 1990:16(3):
4. Darmawan J, Valkenburg H, Muirden KD, Wigley RD. The Epidemiology of Gout and Hyperuricemia in a Rural Population of Java. J Rheumatol 1992;19:1595-9.
5. Darmawan J, Rheumatic Conditions in Nortern Part of Central Java. An Epidemiological Survey. MD Erasmus University Rotterdam, 1988;147-50 (thesis).
6. Chou CT, Pei L, Chang DM, Lee CF, Schumacher HR Jr, Liang MH. Prevalence of Rheumatic Disease in Taiwan: A Population Study of Urban, Suburban, Rural Diggerences. J Rheumatol 1994;21:302-6.
7. Tehupeiory E. Gouty Arthritis and Uric Acid Distribution in Several Ethnic Groups in Ujung Pandang, 1992 (thesis).
8. Padang C, Muirden KD, Schumacher HR. Chronic Tophaceous Gout in the Northern Part of Sulawesi. Proceeding of the Eight APLAR Congress of Rheumatology. Melbourne 1996.
9. Louthrenoo W. Gout Arthritis in the Northern Part of Thailand. Proceeding of the Third ASEAN Congress of Rheumatology, Bangkok, Thailand, 1991.
10. Torralba T, Buenviaga MB, Navarra SV. Some uncommon Clinical Presentation of Gout. Proceeding of the Third ASEAN Congress of Rheumatology, Bangkok, Thailand, 1991.
11. Shahdan MS. Clinical Spectrum of Gout in Malaysia. Proceeding of the Third ASEAN Congress of Rheumatology, Bangkok, Thailand, 1991.
12. Lai YL, Ng SC. Clinical Profile of Gouty arthritis. Fourth ASEA Congres of Rheumatology, Singapore, 1994.
EPIDEMIOLOGY
The prevalence of gout varies from one population to another and within populations between geographical areas. Any assessment of the incidence of gout in any population group will depend upon the criteria used to establish the diagnosis. Previous reports revealed that the incidence of hyperuricemia and gout is higher in a number of Asian races living in the USA than in comparable groups living in their homeland.1 For instance the rate of hyperuricemia and gout among the Filipinos living in Hongkong or in United States is significantly higher than those living in their native countries.1, 2
There is evidence that the distribution of serum uric acid (SUA) has changed, more people are now showing higher SUA levels with subsequent increased risk for gout.3 The three ethnic groups in Malaysia, the Malay (Malayo-Polynesians), Tamils and Chinese (Mongoloid) showed higher mean SUA levels compared with most Caucasian populations. This suggests that the influence of environmental factors might be of significance.4
The WHO-ILAR-COPCORD stage I phase 3 research in Bandungan, central Java, Indonesia, showed that the frequency of hyperuricemia and gout in males 15 years of age and over is high compared with Caucasian population. This is despite a lower life expectancy, low social class, and abstinence of alcohol and subsistence economy. The prevalence of gout was 0.8% in the 4.683 people 15 years and older. The overall male to female ratio was thirty-four to one. Gout occurred in 1.7% of the men and 0.05% of the women. It was predominantly found in men over 45 years. Acute gouty arthritis and chronic tophaceous gout were both found in this population sample.5
In Taiwan, it was found that the incidence of gout in rural and urban area were 13.6/1,000 and 6.4/1,000 respectively while the prevalence of gout were 0.6% (rural) and 0.67% (urban).6 In the clinical study of 45 gout patients in Ujung Pandang (South Sulawesi, Indonesia) the rate of hyperuricemia was 88.0%7 while in North Sulawesi, it was found that among the 208 chronic gout patients, 92.3% had hyperuricemia8. The occurrence of gout was frequent in the patients' family in North Sulawesi.
CLINICAL FEATURES AND COMPLICATIONS
In several Asian countries, the clinical features of gout seem to be different from Western countries. In the northern part of Thailand it was found that of 75 patients analyzed, the mean age was 58 years. The mean duration of disease was 6.7 years. Ankles were the most common sites of attack (45%) followed by first metatarsophalangeal joint (28%) and knee (24%). Tophi were present in 47% with the mean disease duration before onset of tophi was 5.6 years. Fifty five percent had impaired renal function (creatinine > 1.5 mg/dl). Urinary stones were found in 33%, hypertension in 56% and diabetes mellitus in 7% of patients.9 The study of gouty arthritis and uric acid levels in several ethnic groups in Ujung Pandang, South Sulawesi, Indonesia suggest that in Indonesia gout is a common and severe arthritic condition for which patients often present too late for effective treatment. More than 50% of patients with tophi have noted these for 7 – 9 years before coming for their first treatment. Tophaceous gout was not clearly associated with any one ethnic group.7
A study of 190 chronic tophaceous gout patients in North Sulawesi, Indonesia, showed that about 32.2% of patients experienced their first attack of gout when they were less than 34 years old. Multiple tophi and deformities were found in 80% of cases, they had tophi for 5 – 10 years, and kidney stones were found in 12% of cases.
In University Santo Thomas Hospital, Philippines, a study found 6 males developing gout before age 20, 44 patients between 20 - 29 years of age, and another subgroup of 124 males. With disease onset between 30 – 39 years. The youngest male patient was 12 years old. These patients was characterized by an earlier onset of gouty arthritis, with an average age of 20 years, leading to more severe joint involvement and tophaceous deposition, more severe renal damage with kidney stone formation. Uncommon clinical presentation of gout were found in this country, such as those involving pre-menopausal women, early onset in males polyarticular gout, the occurrence of gout with systemic lupus erythematosus and rheumatoid arthritis and some unusual sites of urate deposition.10
In Malaysian study, the clinical features of gout were similar to other Asian countries. Renal stones and positive family history were noticed in 42% and 30% respectively.11 A retrospective study in Alexandria hospital, Singapore, disclosed that 66% of cases (n: 51) were obese with body mass index >25. The commonest joint involvement was MTP I (51%), knees (49%), and ankles (46%). Tophi were noticed in 31% of cases.12
TREATMENT
The COPCORD survey in Indonesia indicated that more than 60% of rheumatic patients had sought help from the rural or urban primary health centers (PHCs), general practitioner, or nurses or primary health care workers. It was also found that 74% of the urban and 71% of the rural population with rheumatism resorted to self medication by buying “over the counter” tablets and capsules. These drugs were found to be prescription drugs containing glucocorticoid or phenylbutazone or a mixture of both. With their spectacular short-term therapeutic relief of joint inflammation and pain these agents are apt to increase in popularity 5. Thiazid diuretics (HCT) are widely used in community health centers in Indonesia.
A study in South Sulawesi revealed that patients first come for treatment after an average of 6.6 years following the first attack of gout.7 A survey in North Sulawesi found that there were no urate lowering drugs available in PHCs in this area. Most patients had never received any adequate treatment for gout.8
CONCLUSION
Based on several studies in some Asia countries, it was found that clinical features of gout seem to be different from Western countries. Gout patients seen in the Philippines and Northern Sulawesi (Indonesia) and northern part of Thailand were younger than other countries.
The duration of gout in Thailand and South Sulawesi (Indonesia) are similar. Overweight was found in the study Singapore and North Sulawesi (Indonesia), however in Thailand, most of gout patients were underweight and malnourished. First attack of gout in most Asian countries such as Indonesia, Singapore was at the first metatarsophalangeal, however in Thailand, the ankle was the most frequently affected joint. Tophi were found in most countries such as Indonesia, Singapore, and Thailand. Hypertension and kidney involvement was reported as the frequent complication in these areas.
Thiazide diuretics were used in the PHCs to treat high blood pressure and were suspected as a risk factor for gout. There was no report from other Asian countries regarding the treatment of gout in their countries.
Further studies are needed to clarify the differences of pattern of gout from one country to another.
REFERENCES
1. Emmerson B.T. Incidence of Gout in Different Populations. Hyperuricemia and Gout in Clinical Practice, 1983:70.
2. Zimmet P.Z, Whitehouse S, Jackson L, Thoma K. High Prevalence of Hyperuricemia and Gout in an Urbanized Micronesian Population. Br Med J 1878;1:1237-9.
3. Roubenoff R. Incidence and Prevalence of Gouty arthritis. Rheum Dis Clin of North America 1990:16(3):
4. Darmawan J, Valkenburg H, Muirden KD, Wigley RD. The Epidemiology of Gout and Hyperuricemia in a Rural Population of Java. J Rheumatol 1992;19:1595-9.
5. Darmawan J, Rheumatic Conditions in Nortern Part of Central Java. An Epidemiological Survey. MD Erasmus University Rotterdam, 1988;147-50 (thesis).
6. Chou CT, Pei L, Chang DM, Lee CF, Schumacher HR Jr, Liang MH. Prevalence of Rheumatic Disease in Taiwan: A Population Study of Urban, Suburban, Rural Diggerences. J Rheumatol 1994;21:302-6.
7. Tehupeiory E. Gouty Arthritis and Uric Acid Distribution in Several Ethnic Groups in Ujung Pandang, 1992 (thesis).
8. Padang C, Muirden KD, Schumacher HR. Chronic Tophaceous Gout in the Northern Part of Sulawesi. Proceeding of the Eight APLAR Congress of Rheumatology. Melbourne 1996.
9. Louthrenoo W. Gout Arthritis in the Northern Part of Thailand. Proceeding of the Third ASEAN Congress of Rheumatology, Bangkok, Thailand, 1991.
10. Torralba T, Buenviaga MB, Navarra SV. Some uncommon Clinical Presentation of Gout. Proceeding of the Third ASEAN Congress of Rheumatology, Bangkok, Thailand, 1991.
11. Shahdan MS. Clinical Spectrum of Gout in Malaysia. Proceeding of the Third ASEAN Congress of Rheumatology, Bangkok, Thailand, 1991.
12. Lai YL, Ng SC. Clinical Profile of Gouty arthritis. Fourth ASEA Congres of Rheumatology, Singapore, 1994.
Colchicine
CATEGORIES, BRAND NAMES, FORMULARIES & COST OF THERAPY
CATEGORIES: Antigout; Arthritis; Back Pain; Electrolytic, Caloric-Water Balance; FDA Pre 1938 Drugs; Gout; Gouty Arthritis; HCFA Code J0760 (Injection up to 2 mg); Pain; Pregnancy Category D; Top 800 Drugs; Uricosuric Agents
BRAND NAMES: Artrichine*; Colchimedio*; Colchineos*; Colgout*; Colsalide Improved; Coluric*; Conicine*
* Foreign brand name outside U.S.
FORMULARIES: Aetna; BC/BS; FHP; Medi-Cal; WHO
DESCRIPTION
This product is to be used by or under the direction of a physician.
A phenanthrene derivative, colchicine is the active alkaloidal principle derived from various species of Colchicum; it appears as pale-yellow amorphous scales or powder that darkens on exposure to light. One g dissolves in 25 ml of water and in 220 ml of ether. Colchicine is freely soluble in alcohol and chloroform.
Chemically it is Acetamide, N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo(alpha)heptalen-7-yl)-,(S)-. The molecular weight is 399.44, the empirical formula is C22H25NO6.
Colchicine, an acetyltrimethylcolchicinic acid, is hydrolyzed in the presence of dilute acids or alkalies, with cleavage of a methyl group as methanol and formation of colchiceine, which has very little therapeutic activity. On hydrolysis with strong acids, colchicine is converted to trimethylcolchicinic acid.
Ampoules Colchicine Injection, USP, provide a sterile aqueous solution of colchicine for intravenous use. Each ampoule contains 1 mg (2.5 µmol) of colchicine in 2 ml of solution. Sodium hydroxide may have been added during manufacture to adjust the pH.
CLINICAL PHARMACOLOGY
The mechanism of the relief afforded by colchicine in acute attacks of gouty arthritis is not completely known, but studies on the processes involved in precipitation of an acute attack have helped elucidate how this drug may exert its effects. The drug is not an analgesic, does not relieve other types of pain or inflammation, and is of no value in other types of arthritis. It is not a diuretic and does not influence the renal excretion of uric acid or its level in the blood or the magnitude of the "miscible pool" of uric acid. It also does not alter the solubility of urate in the plasma.
Colchicine is not a uricosuric agent. An acute attack of gout apparently occurs as a result of an inflammatory reaction to crystals of monosodium urate that are deposited in the joint tissue from hyperuric body fluids; the reaction is aggravated as more urate crystals accumulate. The initial inflammatory response involves local infiltration of granulocytes that phagocytize the urate crystals. Interference with these processes will prevent the development of an acute attack. Colchicine apparently exerts its effect by reducing the inflammatory response to the deposited crystals and also by diminishing phagocytosis. The deposition of uric acid is favored by an acid pH. In synovial tissues and in leukocytes associated with inflammatory processes, lactic acid production is high; this favors a local decrease in pH that enhances uric acid deposition. Colchicine diminishes lactic acid production by leukocytes both directly and by diminishing phagocytosis, thereby interrupting the cycle of urate crystal deposition and inflammatory response that sustains the acute attack. The oxidation of glucose in phagocytizing as well as in nonphagocytizing leukocytes in vitro is suppressed by colchicine; this suppression may explain the diminished lactic acid production. The precise biochemical step that is affected by colchicine is not yet known. The antimitotic activity of colchicine is unrelated to its effectiveness in the treatment of acute gout, as indicated by the fact that trimethylcolchicinic acid, an analog of colchicine, has no antimitotic activity except in extremely high doses.
INDICATIONS
Colchicine is indicated for the treatment of gout. It is effective in relieving the pain of acute attacks, especially if therapy is begun early in the attack and in adequate dosage. Many therapists use colchicine as interval therapy to prevent acute attacks of gout. It has no effect on nongouty arthritis or on uric acid metabolism.
The intravenous use of colchicine is advantageous when a rapid response is desired or when gastrointestinal side effects interfere with oral administration of the medication. Occasionally, intravenous colchicine is effective when the oral preparation is not. After the acute attack has subsided, the patient can usually be given colchicine tablets by mouth.
CONTRAINDICATION
Colchicine is contraindicated in patients with gout who also have serious gastrointestinal, renal, hepatic, or cardiac disorders. Colchicine should not be given in the presence of combined renal and hepatic disease.
WARNING
Colchicine can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking it, the woman should be apprised of the potential hazard to the fetus.
Mortality Related to Overdosage - Cumulative intravenous doses of colchicine above 4 mg hav resulted in irreversible multiple organ failure and death (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).
PRECAUTIONS
General
Reduction in dosage is indicated if weakness, anorexia, nausea, vomiting or diarrhea occurs. Rarely, thrombophlebitis occurs at the site of injection. Colchicine should be with great caution to aged and debilitated patients, especially those with renal, hepatic, gastrointestinal, or heart disease.
Usage in Pregnancy
Pregnancy Category D. See WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when colchicine is administered to a nursing woman.
Usage in Children
Safety and effectiveness in children have not been established.
DRUG INTERACTION
Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. The possibility that colchicine may increase response to central nervous system depressants and to sympathomimetic agents is suggested by the results of experiments on animals.
ADVERSE REACTIONS
These are usually gastrointestinal in nature and consist of abdominal pain, nausea, vomiting, and diarrhea. The diarrhea may be severe. The gastrointestinal symptoms may occur even though the drug is given intravenously; however, such symptoms are unusual unless the recommended dose is exceeded.
Prolonged administration may cause bone marrow depression, with agranulocytosis, thrombocytopenia, and aplastic anemia. Peripheral neuritis and epilation have also been reported.
Myopathy may occur in patients on usual maintenance doses, especially in the presence of renal impairment.
OVERDOSAGE
Signs and Symptoms
Symptoms, the onset of which may be delayed, include nausea, vomiting, diarrhea, abdominal pain, hemorrhagic gastroenteritis, and burning pain in the throat, stomach, and skin. Fluid extravasation may lead to shock. Myocardial injury may be accompanied by ST-segment elevation, decreased contractility, and profound shock. Muscle weakness or paralysis may occur and progress to respiratory failure. Hepatocellular damage, renal failure, and lung parenchymal infiltrates may occur and, by the fifth day after overdose, leukopenia, thrombocytopenia, and coagulopathy may also occur. if the patient survives, alopecia and stomatitis may be experienced. There is no clear separation of nontoxic, toxic, and lethal doses of colchicine. The lethal dose of colchicine has been estimated to be 65 mg; however, death has resulted from intravenous doses as small as 7 mg acutely (see WARNINGS and DOSAGE AND ADMINISTRATION). Serum concentrations that may be toxic or lethal are not defined. The intravenous median lethal dose in rats is 1.7 mg/kg.
Treatment
To obtain up-to-date information about the treatment of overdose, a good resource is your certified REGIONAL POISON CONTROL CENTER. Telephone numbers certified poison control centers are listed in the Physicians GenRX (PGRX). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. If colchicine was recently ingested and vomiting has not occurred, perform gastric lavage once the patient is stabilized. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of colchicine.
DOSAGE AND ADMINISTRATION
Colchicine Injection is for intravenous use only. Severe local irritation occurs if it is administered subcutaneously or intramuscularly.
It is extremely important that the needle be properly positioned in the vein before colchicine is injected. If leakage into surrounding tissue or outside the vein along its course should occur during intravenous administration, considerable irritation and possible tissue damage may follow. There is no specific antidote for the prevention of this irritation. Local application of heat or cold, as well as the administration of analgesics, may afford relief.
The injection should take 2 to 5 minutes for completion. To minimize the risk of extravasation, it is recommended that the injection be made into an established intravenous line into a large vein using normal saline as the intravenous fluid. Colchicine Injection should not be diluted with 5% Dextrose in Water. If a decrease in concentration of colchicine in solution is required, 0.9% Sodium Chloride Injection, which does not contain a bacteriostatic agent, should be used. Solutions that become turbid should not be used.
In the treatment of acute gouty arthritis, rhe average initial dose of Colchicine Injection is 2 mg (4 ml). This may be followed by 0.5 (1 ml) every 6 hours until a satisfactory response is achieved. In general, a total dosage for the first 24-hour period should is achieved. In general, the total dosage for the first 24-hour period should not exceed 4 mg (8 ml). Cumulative doses of colchicine above 4 mg have resulted in irreversible multiple organ failure and death. The total dosage for a single course of treatment should not exceed 4 mg. Some clinicians recommend a single intravenous dose of 3 mg, whereas others recommend an initial dose of not more than 1 mg of colchicine intravenously, followed by 0.5 mg once or twice daily if needed.
If pain recurs, it may be necessary to administer a daily dose of 1 to 2 mg (2 to 4 ml) for several days; however, no more colchicine should be given by any route for at least 7 days after a full course of IV therapy (4 mg).1,2 Many patients can be transferred to oral colchicine at a dosage similar to that being given intravenously.
In the prophylactic or maintenance therapy of recurrent or chronic gouty arthritis, a dosage of 0.,5 to 1 mg (1 to 2 ml) once or twice daily may be used. However, in these cases, oral administration of colchicine is preferable, usually taken in conjunction with a uricosuric agent. If an acute attack of gout occurs while the patient is taking colchicine as maintenance therapy, an alternative drug should be instituted in preference to increasing the dose of colchicine.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Storage
Store at controlled room temperature, 59 to 86oF (15 to 30oC).
REFERENCE
1. Wallace SL, Singer JZ: Review: systemic toxicity associated with the intravenous administration of colchicine - guidelines for use. J Rheumatol 1988; 15:495-499.
2. Simons RJ, Kingma DW: Fatal colchicine toxicity. Am J Med 1989; 86:356-357.
HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE:
Injection, Solution - Intravenous - 1 mg/2ml
2 ml x 6 $19.55 Colchicine, Lilly 00002-1443-16
Tablet, Uncoated - Oral - 0.5 mg
100's $26.03 Colchicine, Abbott 00074-0074-02*
Tablet, Uncoated - Oral - 0.6 mg
100's $3.80 Colchicine, West-Ward Pharm 00143-1201-01
100's $4.25 Colchicine, Schein Pharm 00364-0074-01
100's $4.30 Colchicine, Major Pharm 00904-2047-60
100's $4.60 Colchicine, United Res Labs 00677-0040-01
100's $4.70 Colchicine, Qualitest Products 00603-3052-21
100's $5.00 Colchicine, Zenith Labs 00172-2047-60
100's $5.00 Colchicine, Trinity Tech 61355-0001-10
100's $5.78 Colchicine, U.D., Us Trading 56126-0472-11
100's $19.95 Colchicine, Abbott 00074-3781-01*
250's $7.45 Colchicine, Major Pharm 00904-2047-70
1000's $16.80 Colchicine, West-Ward Pharm 00143-1201-10
1000's $17.47 Colchicine, Aligen 00405-4266-03
1000's $18.90 Colchicine, Rugby 00536-3494-10
1000's $19.60 Colchicine, Schein Pharm 00364-0074-02
1000's $19.90 Colchicine, Qualitest Products 00603-3052-32
1000's $20.30 Colchicine, United Res Labs 00677-0040-10
1000's $20.39 Colchicine, Moore Drug Exch 00839-5152-16
1000's $21.40 Colchicine, Major Pharm 00904-2047-80
1000's $23.60 Colchicine, Zenith Labs 00172-2047-80
1000's $23.60 Colchicine, Goldline Labs 00182-0174-10
1000's $23.60 Colchicine, Trinity Tech 61355-0001-11
1000's $88.12 Colchicine, Lilly 00002-1013-04*
Tablet, Uncoated - Oral - 1 mg
100's $3.95 Colchicine, Consolidated Mc 00223-0703-01
1000's $19.75 Colchicine, Consolidated Mc 00223-0703-02
CATEGORIES: Antigout; Arthritis; Back Pain; Electrolytic, Caloric-Water Balance; FDA Pre 1938 Drugs; Gout; Gouty Arthritis; HCFA Code J0760 (Injection up to 2 mg); Pain; Pregnancy Category D; Top 800 Drugs; Uricosuric Agents
BRAND NAMES: Artrichine*; Colchimedio*; Colchineos*; Colgout*; Colsalide Improved; Coluric*; Conicine*
* Foreign brand name outside U.S.
FORMULARIES: Aetna; BC/BS; FHP; Medi-Cal; WHO
DESCRIPTION
This product is to be used by or under the direction of a physician.
A phenanthrene derivative, colchicine is the active alkaloidal principle derived from various species of Colchicum; it appears as pale-yellow amorphous scales or powder that darkens on exposure to light. One g dissolves in 25 ml of water and in 220 ml of ether. Colchicine is freely soluble in alcohol and chloroform.
Chemically it is Acetamide, N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo(alpha)heptalen-7-yl)-,(S)-. The molecular weight is 399.44, the empirical formula is C22H25NO6.
Colchicine, an acetyltrimethylcolchicinic acid, is hydrolyzed in the presence of dilute acids or alkalies, with cleavage of a methyl group as methanol and formation of colchiceine, which has very little therapeutic activity. On hydrolysis with strong acids, colchicine is converted to trimethylcolchicinic acid.
Ampoules Colchicine Injection, USP, provide a sterile aqueous solution of colchicine for intravenous use. Each ampoule contains 1 mg (2.5 µmol) of colchicine in 2 ml of solution. Sodium hydroxide may have been added during manufacture to adjust the pH.
CLINICAL PHARMACOLOGY
The mechanism of the relief afforded by colchicine in acute attacks of gouty arthritis is not completely known, but studies on the processes involved in precipitation of an acute attack have helped elucidate how this drug may exert its effects. The drug is not an analgesic, does not relieve other types of pain or inflammation, and is of no value in other types of arthritis. It is not a diuretic and does not influence the renal excretion of uric acid or its level in the blood or the magnitude of the "miscible pool" of uric acid. It also does not alter the solubility of urate in the plasma.
Colchicine is not a uricosuric agent. An acute attack of gout apparently occurs as a result of an inflammatory reaction to crystals of monosodium urate that are deposited in the joint tissue from hyperuric body fluids; the reaction is aggravated as more urate crystals accumulate. The initial inflammatory response involves local infiltration of granulocytes that phagocytize the urate crystals. Interference with these processes will prevent the development of an acute attack. Colchicine apparently exerts its effect by reducing the inflammatory response to the deposited crystals and also by diminishing phagocytosis. The deposition of uric acid is favored by an acid pH. In synovial tissues and in leukocytes associated with inflammatory processes, lactic acid production is high; this favors a local decrease in pH that enhances uric acid deposition. Colchicine diminishes lactic acid production by leukocytes both directly and by diminishing phagocytosis, thereby interrupting the cycle of urate crystal deposition and inflammatory response that sustains the acute attack. The oxidation of glucose in phagocytizing as well as in nonphagocytizing leukocytes in vitro is suppressed by colchicine; this suppression may explain the diminished lactic acid production. The precise biochemical step that is affected by colchicine is not yet known. The antimitotic activity of colchicine is unrelated to its effectiveness in the treatment of acute gout, as indicated by the fact that trimethylcolchicinic acid, an analog of colchicine, has no antimitotic activity except in extremely high doses.
INDICATIONS
Colchicine is indicated for the treatment of gout. It is effective in relieving the pain of acute attacks, especially if therapy is begun early in the attack and in adequate dosage. Many therapists use colchicine as interval therapy to prevent acute attacks of gout. It has no effect on nongouty arthritis or on uric acid metabolism.
The intravenous use of colchicine is advantageous when a rapid response is desired or when gastrointestinal side effects interfere with oral administration of the medication. Occasionally, intravenous colchicine is effective when the oral preparation is not. After the acute attack has subsided, the patient can usually be given colchicine tablets by mouth.
CONTRAINDICATION
Colchicine is contraindicated in patients with gout who also have serious gastrointestinal, renal, hepatic, or cardiac disorders. Colchicine should not be given in the presence of combined renal and hepatic disease.
WARNING
Colchicine can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking it, the woman should be apprised of the potential hazard to the fetus.
Mortality Related to Overdosage - Cumulative intravenous doses of colchicine above 4 mg hav resulted in irreversible multiple organ failure and death (see OVERDOSAGE and DOSAGE AND ADMINISTRATION).
PRECAUTIONS
General
Reduction in dosage is indicated if weakness, anorexia, nausea, vomiting or diarrhea occurs. Rarely, thrombophlebitis occurs at the site of injection. Colchicine should be with great caution to aged and debilitated patients, especially those with renal, hepatic, gastrointestinal, or heart disease.
Usage in Pregnancy
Pregnancy Category D. See WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when colchicine is administered to a nursing woman.
Usage in Children
Safety and effectiveness in children have not been established.
DRUG INTERACTION
Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. The possibility that colchicine may increase response to central nervous system depressants and to sympathomimetic agents is suggested by the results of experiments on animals.
ADVERSE REACTIONS
These are usually gastrointestinal in nature and consist of abdominal pain, nausea, vomiting, and diarrhea. The diarrhea may be severe. The gastrointestinal symptoms may occur even though the drug is given intravenously; however, such symptoms are unusual unless the recommended dose is exceeded.
Prolonged administration may cause bone marrow depression, with agranulocytosis, thrombocytopenia, and aplastic anemia. Peripheral neuritis and epilation have also been reported.
Myopathy may occur in patients on usual maintenance doses, especially in the presence of renal impairment.
OVERDOSAGE
Signs and Symptoms
Symptoms, the onset of which may be delayed, include nausea, vomiting, diarrhea, abdominal pain, hemorrhagic gastroenteritis, and burning pain in the throat, stomach, and skin. Fluid extravasation may lead to shock. Myocardial injury may be accompanied by ST-segment elevation, decreased contractility, and profound shock. Muscle weakness or paralysis may occur and progress to respiratory failure. Hepatocellular damage, renal failure, and lung parenchymal infiltrates may occur and, by the fifth day after overdose, leukopenia, thrombocytopenia, and coagulopathy may also occur. if the patient survives, alopecia and stomatitis may be experienced. There is no clear separation of nontoxic, toxic, and lethal doses of colchicine. The lethal dose of colchicine has been estimated to be 65 mg; however, death has resulted from intravenous doses as small as 7 mg acutely (see WARNINGS and DOSAGE AND ADMINISTRATION). Serum concentrations that may be toxic or lethal are not defined. The intravenous median lethal dose in rats is 1.7 mg/kg.
Treatment
To obtain up-to-date information about the treatment of overdose, a good resource is your certified REGIONAL POISON CONTROL CENTER. Telephone numbers certified poison control centers are listed in the Physicians GenRX (PGRX). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. If colchicine was recently ingested and vomiting has not occurred, perform gastric lavage once the patient is stabilized. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of colchicine.
DOSAGE AND ADMINISTRATION
Colchicine Injection is for intravenous use only. Severe local irritation occurs if it is administered subcutaneously or intramuscularly.
It is extremely important that the needle be properly positioned in the vein before colchicine is injected. If leakage into surrounding tissue or outside the vein along its course should occur during intravenous administration, considerable irritation and possible tissue damage may follow. There is no specific antidote for the prevention of this irritation. Local application of heat or cold, as well as the administration of analgesics, may afford relief.
The injection should take 2 to 5 minutes for completion. To minimize the risk of extravasation, it is recommended that the injection be made into an established intravenous line into a large vein using normal saline as the intravenous fluid. Colchicine Injection should not be diluted with 5% Dextrose in Water. If a decrease in concentration of colchicine in solution is required, 0.9% Sodium Chloride Injection, which does not contain a bacteriostatic agent, should be used. Solutions that become turbid should not be used.
In the treatment of acute gouty arthritis, rhe average initial dose of Colchicine Injection is 2 mg (4 ml). This may be followed by 0.5 (1 ml) every 6 hours until a satisfactory response is achieved. In general, a total dosage for the first 24-hour period should is achieved. In general, the total dosage for the first 24-hour period should not exceed 4 mg (8 ml). Cumulative doses of colchicine above 4 mg have resulted in irreversible multiple organ failure and death. The total dosage for a single course of treatment should not exceed 4 mg. Some clinicians recommend a single intravenous dose of 3 mg, whereas others recommend an initial dose of not more than 1 mg of colchicine intravenously, followed by 0.5 mg once or twice daily if needed.
If pain recurs, it may be necessary to administer a daily dose of 1 to 2 mg (2 to 4 ml) for several days; however, no more colchicine should be given by any route for at least 7 days after a full course of IV therapy (4 mg).1,2 Many patients can be transferred to oral colchicine at a dosage similar to that being given intravenously.
In the prophylactic or maintenance therapy of recurrent or chronic gouty arthritis, a dosage of 0.,5 to 1 mg (1 to 2 ml) once or twice daily may be used. However, in these cases, oral administration of colchicine is preferable, usually taken in conjunction with a uricosuric agent. If an acute attack of gout occurs while the patient is taking colchicine as maintenance therapy, an alternative drug should be instituted in preference to increasing the dose of colchicine.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Storage
Store at controlled room temperature, 59 to 86oF (15 to 30oC).
REFERENCE
1. Wallace SL, Singer JZ: Review: systemic toxicity associated with the intravenous administration of colchicine - guidelines for use. J Rheumatol 1988; 15:495-499.
2. Simons RJ, Kingma DW: Fatal colchicine toxicity. Am J Med 1989; 86:356-357.
HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE:
Injection, Solution - Intravenous - 1 mg/2ml
2 ml x 6 $19.55 Colchicine, Lilly 00002-1443-16
Tablet, Uncoated - Oral - 0.5 mg
100's $26.03 Colchicine, Abbott 00074-0074-02*
Tablet, Uncoated - Oral - 0.6 mg
100's $3.80 Colchicine, West-Ward Pharm 00143-1201-01
100's $4.25 Colchicine, Schein Pharm 00364-0074-01
100's $4.30 Colchicine, Major Pharm 00904-2047-60
100's $4.60 Colchicine, United Res Labs 00677-0040-01
100's $4.70 Colchicine, Qualitest Products 00603-3052-21
100's $5.00 Colchicine, Zenith Labs 00172-2047-60
100's $5.00 Colchicine, Trinity Tech 61355-0001-10
100's $5.78 Colchicine, U.D., Us Trading 56126-0472-11
100's $19.95 Colchicine, Abbott 00074-3781-01*
250's $7.45 Colchicine, Major Pharm 00904-2047-70
1000's $16.80 Colchicine, West-Ward Pharm 00143-1201-10
1000's $17.47 Colchicine, Aligen 00405-4266-03
1000's $18.90 Colchicine, Rugby 00536-3494-10
1000's $19.60 Colchicine, Schein Pharm 00364-0074-02
1000's $19.90 Colchicine, Qualitest Products 00603-3052-32
1000's $20.30 Colchicine, United Res Labs 00677-0040-10
1000's $20.39 Colchicine, Moore Drug Exch 00839-5152-16
1000's $21.40 Colchicine, Major Pharm 00904-2047-80
1000's $23.60 Colchicine, Zenith Labs 00172-2047-80
1000's $23.60 Colchicine, Goldline Labs 00182-0174-10
1000's $23.60 Colchicine, Trinity Tech 61355-0001-11
1000's $88.12 Colchicine, Lilly 00002-1013-04*
Tablet, Uncoated - Oral - 1 mg
100's $3.95 Colchicine, Consolidated Mc 00223-0703-01
1000's $19.75 Colchicine, Consolidated Mc 00223-0703-02
Chronic Tophaceous Gout: Risk Factors For The Development of Tophi
What is gout?
Gouty arthritis by definition implies to a condition of joint inflammation due to the deposition of monosodium urat (MSU) crystal.1
Acute joint inflammation usually affecting the first metatarso-phalangeal joint referred to a very painful, redness and swollen joint that subsequently subsided within 5 to 10 days with or without medication. This condition recurred several times and between two acute episodes the patient beyond an intercritical phase. In other rare cases or chronic phase, several joints (polyarthritis) could be affected simultaneously.2,3 Recurrent attack and further deposition of MSU crystal will lead to a chronic condition and tophi develop.4,5,6 The deposition of tophi in the joint and bone will cause a serious damage to its structure and leading to deformities. Usually the development of tophi has a correlation with the severity of gout.
Epidemiology
The prevalence of hyperuricemia, gout and chronic tophaceous gout varies between countries.7 The WHO-ILAR-COPCORD stage I phase 3 researches in Bandungan, central Java, Indonesia, showed that the prevalence rate of gout and hyperuricemia in males 15 years of age and over is high compared to Caucasian populations. The prevalence of gout was 0.8% in the 4,683 people 15 years and older. Gout occurred in 1.7% of the men and 0.05% of the women. Acute gouty arthritis and chronic tophaceous gout were both found in the population sample.8 In Great Britain, the annual incidence rate (1971-1975), varying from 0.25 to 0.35 per 1000 and the prevalence of primary gout was estimated to be 2.3 per 1000.9 While in Taiwan the prevalence of gout was 0.60% in the rural area and 0.67% in the urban area.10 Another study from Indonesia, in northern part of Sulawesi indicating that chronic tophaceous gout was commonly seen among the population. Around 80% in the 208 population samples has developed tophi and various deformities.11 While in United State (USA) 35% in the 60 patients with gout also had tophi and deformities.12 A higher percentage compared to USA, 47% of 75 gouty arthritic patients in Thailand also developed tophi.13
Gouty arthritis was common in men rather than women. Previously, this disease was well known as the disease of King and the king of diseases. A bit different in sex differences founded in Polynesian women. Among them the differences to have hyperucicemia and gout was similar with those founded in men. This is to be believed caused by genetic defect in renal urate handling beside the occurrence of high purine intake and obesity.14
Factors affecting the formation of tophi
Hyperuricemia
A very high concentration of serum uric acid (SUA) always in correlation with the development of tophi. Tophus will be developed if the SUA level greater than 10 mg/dl. 4,5
The uric acid pool in patients with chronic tophaceous gout ranging between 18,000 – 31,000 mg. While in non tophaceous gouty arthritic patients the pool of uric acid is much lesser than the patients with tophus that is 2,400 – 3,600 mg. The uric acid pool was more than ten fold compared to normal person (1,200 mg). It is understandable why the patient with tophus will have an acute attack more frequent than those without tophus. This consideration derived from the fact that only a small amount of uric acid from the pool will be dissolved and excreted every day. 15
Genetic
A substantial part of gouty arthritic patients is a defect in purine metabolism, which is characterized by the increasing of purine synthesis, and it was abnormal. The acceleration of biosynthesis pointed to the genetic changes. Cassim B et al of Congella, South Africa founded that there was an increased in frequency of HLA-B14 in patients with primary gout but clinical significance of this is uncertain.16 The genetic defect resulting in disturbances of purine synthesis control mechanism.17 The most common abnormalities as a result in genetic changes were enzyme deficiency. It is Hypoxanthine guanine phosphoribocyl transferase (HPRT) as the main enzyme in regulating the purine synthesis. The HPRT deficiency will cause hyperuricemia.
The duration of having gouty arthritis
The development of tophus depends on the interval from the first attack of acute gout and it is lies between 3 – 42 years after the onset of gout. Becker and Levinson 4,5 found that tophus will be developed after 11.6 years of the onset of gout, while Nakayama et al 12 found the longer period around 18-19 years after. A few severe cases demonstrated that tophus already exist at the first acute attack of gout.18 This condition occur in a condition where the patient having renal problem, older age, on diuretic treatment and frequent use of non-steroidal anti-inflammatory drugs (NSAIDs). 19,20,21,22,23 Organ transplantation and the use of immunosuppressive agent such as cyslosporine-A was another factor for the formation of tophus at the first acute attack of gout.24
Obesity
Obesity was in correlation with the over production of uric acid and decreases of uric acid excretion. A low purine diet and weight loss program will improve the excretion of uric acid.1, 25,26 Dessein et al showed a beneficial effect of weight loss associated with moderate calorie / carbohydrate restriction (40%), and increases proportional intake of protein (30%) and fat (30%).27
Alcohol consumption
An alcoholic more prone to have gouty arthritis. The alcohol and its relationship with the incidence of gout could be arising from two different ways. The first, alcohol will increase the production of uric acid. Several kinds of alcohol beverages have a very high pure content. 28,29 The principle constituent found to be guanosine, which is probably the most readily absorbed dietary purine.30 Secondly, alcohol will decrease the excretion of uric acid.1,30 The second mechanism still on debatable. There is no evidence that beer taken in usual quantities will reduce the renal excretion of uric acid.30
In alcoholic gouty arthritic patients, the acute attack occurs in lower concentration of SUA in comparison to non-alcoholic gout patients.31
Purine intake
An abundant of purine consumption will lead to the overproduction of uric acid and at prolonged time will cause hyperuricemia uncontrollable and increasing the possibilities of deposition of uric acid crystal.1,4,5,32 Low purine diet will bring the SUA level to 15% lesser than normal diet.4
Dyslipidemia
Hypertriglyceridemia frequently found with gouty arthritis.4,33 Kelley and Wortman founded that lipid abnormalities among patients with gout was 75-84%.2 While Becker and Levinson founded hypertriglyceridemia in 50-75% of gouty arthritic patients.5
The mechanism of two differently metabolic abnormalities is not clearly understood. One study conducted by Moriwaki Y et al showed that there is a disturbance in apolipoprotein-e4 (apo-e4) allel.34 The apo-e is important in coating process of MSU crystal. The apo-e-coated MSU crystal will inhibit the inflammatory process in the synovium.
Renal function
Renal function is important in handling uric acid. Almost all of SUA will be filtrated in glomerulus and will be reabsorbed in renal tubule, so only a small amount of SUA will be excreted in the urine. Diminished renal function with the excretion less than 600 mg/dl a day will lead to hyperuricemia. It cannot compensate the production rate of SUA.1,4,32,35 This condition mostly has a genetic basis,36 and in the others there is the influences of drugs such as diuretics, pyrazinamide and ethambuthol. 37,38,39 Another factor should be in our mind that would be a major contributor of hyperuricemia and gout was the primary renal disease. 40,41,42,
Drugs
Many drugs could have its potentiality altering the renal function particularly in long-term therapy. The most common drug associated with the development of tophi was diuretic. A study on gout in Great Britain demonstrated that the elderly women are prone to diuretic-induced tophaceous gout but less likely to present with acute gout than man.43 Scott JT and Higgens CS founded that in diuretic induced gout there was one or more additional factors were present.23
Non-compliance to treatment
The invention of urate lowering drugs such as uricosuric agent or xanthine oxydase inhibitor (i.e allopurinol) is a remarkable inventory and brings the incidence of tophus down from 53% to 17%.5,24 In fact, many studies on gout still reported the high incidence of tophus. Nakayama et al 12 reported 35% of gout patients having tophus, and Louthrenoo reported a higher number, that is 47%.13 This condition is closely related to non-compliance to treatment.4,5,12,13
Other rheumatic disease associated with gout
The coincidence of other rheumatic disease with gout is well documented. In Systemic lupus erythematosus (SLE) the association of hyperuricemia and gout was closely associated with renal involvement particularly proteinuria and diuretic therapy.44 While in Rheumatoid arthritis (RA) the coexistence with gout is a questioned, more over with tophaceous gout. There is hypothesis that rheumatoid factor could inhibit the surface activity of monosodium urate crystals.46
Summary
Gout is a uric acid metabolism abnormality and known as one of the painful rheumatic disease. It has genetic basis. The chronic stage leading to joint and bone deformities known as chronic tophaceous gout. The incidence and prevalence of tophus varies between countries or from population to another within country. Hyperuricemia, renal function, non-compliance to treatment, alcohol consumption, obesity, hypertryglyceridemia, and duration of gout is a well-known risk factor for the development of tophus.
References
1. Emerson BT. Management of Gout. N Eng J Med 1996;334:445-51.
2. Perkins P, Jones AC. Gout. Ann Rheum Dis 1999;58:611-6.
3. Raddatz DA, Mahowald ML, Bilka PJ. Acute polyarticular gout. Ann Rheum Dis 1983;42:117-22.
4. Kelley WN, Wortman RL. Gout and hyperuricemia. In: Kelley WN, Harris ED, Ruddy S, Sledge CB eds. Textbook of Rheumatology 5th ed. WB Saunders Co. Philadelphia 1997;1313-51.
5. Becker MA, Levinson DJ. Clinical gout and the pathogenesis of hyperuricemia, In: Kopman WJ eds. Textbook of Rheumatology 13th ed. Williams and Wilkins. Baltimore 1997;2041-2101.
6. Tate G, Schumacher HR. Stages of gout. In: Schumacher HR, Klipel JH, Robinson DR, eds. Primer on the rheumatic disease 9th ed. Arthritis foundation. Atlanta GA 1998;195-206.
7. Darmawan J, Valkenburg HA, Muirden KD, Wigley RD. The epidemiology of gour and gyperuricemia in rural population of Java. J Rheumatol 1992; 1595-9.
8. Darmawan J. Rheumatic conditions in northern part of central Java. An epidemiological survey. MD Erasmus University Rotterdam, 1988;147-50 (thesis).
9. Currie WJ. Prevalence and incidence of the diagnosis of gout in Great Britain. Ann Rheum Dis 1979;38:101-6.
10. Chou CT, Pei L, Chang DM, Lee FC, Schumacher Jr HR, Liang MH. Prevalence of rheumatic disease in Taiwan: A population study of urban, suburban, rural differences. J Rheumatol 1994;21:302-6.
11. Padang C, Muirden KD, Schumacher HR. Chronic tophaceous gout in the northern part of Sulawesi. Proceeding of the eight APLAR Congress of Rheumatology. Melbourne 1996.
12. Nakayama DA, Bartheleny C, Carrera G, Lightfoot RW, Wortmann RL. Tophaceous gout: a clinical and radiographic assessment. Arthritis Rheum 1984;468-71.
13. Louthenoo W. Gouty arthritis in the northern part of Thailand. Proceeding of the third ASEAN Congress of Rheumatology, Bangkok, Thailand 1991.
14. Simmonds HA, McBride MB, Gatfield PJ, Graham R, McCaskey J, Jackson M. Polynesian women are also at risk for hyperuricemia and gout because of genetic defect in renal urate handling. Br J Rheumatol 1994;33:932-7.
15. Boss GR, Seegmiller JE. Hyperuricemia and gout. Classification, complication and management. N Eng J Med 300;26:1459-68
16. Cassim B, Mody GM, Deenadayalu VK, Hammond MG. Gout in black South Africans: a clinical and genetic study. Ann Rheum Dis 1994;53:759-62.
17. Kelley WN, Greene ML, Rosenbloom FW et al. Hypoxanthine-guanine phosphoribocyl transferase deficiency in gout. Ann Int Med 1969;70:155-94.
18. Wernick R, Winkler C, Campbell S. Tophi as the initial manifestation of gout. Arch Int Med 1992;152:873-6.
19. Pulg JG, Michan AD, Jimenez ML et al. Female gout. Clinical spectrum and uric acid metabolism. Arch Int Med 1991; 151:726-32.
20. Lally EV, Hogh JR, Kaplan SR. The clinical spectrum of gouty arthritis in women. Arch Int Med 1986;146:2221-5
21. Simkin PA, Campbell PM, Larson EB. Gout in Heberdens Nodes. Arthritis Rheum 1983;26:94-7
22. Mc Farlane DG, Dieppe PA. Diuretic induced gout in elderly woman. Br J Rheumatol 1985;155-7.
23. Scott TJ, Higgens CS. Diuretic induced gout: A multifactorial condition. Ann Rheum Dis 1992;259-61.
24. Roubenoff R, Klag MJ, Mead LA et al. Incidence and risk factors for gout in white man. JAMA 1991;304-7.
25. Emmerson BT. Alteration of urate metabolism by weight reduction. Aust NZ J Med 1973;410-2.
26. Faller J, Fox JH. Ethanol induced hyperuricemia: Evidence for increased urate production by activation of adenine nucleotide turn over. N Eng J Med 1982; 1598-602.
27. Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie / carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoproteion levels in gout: a pilot study. Ann Rheum Dis 2000;59:539-43.
28. Eastmond CJ, Garton M, Robins S, Riddoch S. The effects of alcoholic beverages on urate metabobilsm in gout sufferes. Br J Rheumatol 1995;34:756-9.
29. Gibson T, Rodgers AV, Simmonds HA, Court-Brown F, Todd E, Meilton V. A controlled study of diet in patients with gout. Ann Rheum Dis 1983;42:123-7.
30. Gibson I, Rodgers AV, Simmonds HA, Toseland P. Beer drinking and its effect on uric acid. Br J Rheumatol 1984;203-9.
31. Vandenberg MK, Moxley G, Breitbach SA, Roberts WN. Gout attacks in chronic alcoholic occur at lower serum level than in non alcoholic. J Rheumatol 1994;700-4.
32. Maclachlan MJ, Rodman GP. Effect of food, fat and alcohol on serum uric acid and acute attack of gout. Am J Med 1967;38-57.
33. Holmes EW, Kelley WN, Wyngaarden JB. The kidney and uric acid excretion in man. Kidney Int 1972;115-8.
34. Moriwaki Y, Yamamoto T, Takahashi S, Tsutsumi Z, Higashino K. Apolipoprotein E phenotypes in patients with gout: relation with hypertriglyceridaemia. Ann Rheum Dis 1995;54:351-4.
35. Grayzel AL, Liddle I, Seegmiller JE. Diagnostic significance of hyperuricemia in arthritis. N Eng J Med 1961;763-8.
36. Postlewaite AE, Bartel AG, Kelley WN. Hyperuricemia due to ethambutol. N Eng J Med 1972;761-2.
37. Star VL, Hochberg MC. Gout: Prevention and management. Medical Progress 1984;47-52.
38. Sew Hoy MD. Gout: Common sense management. Mediacal progress 1991;47-52.
39. Bull PW, Scott JT. Intermittent control of hyperuricemia in the treatment of gout. J Rheumatol 1989;1246-8.
40. Vecchio PC, Emmerson BT. Gout due to renal disease. Br J Rheumatol 1992;31:63-65.
41. Gibson T, Waterworth R, Hatfield P, Robinson G, Bremner K. Hyperuricaemia, gout and kidney function in New Zealand Maori Men. Br J Rheumatol 1984;23:276-82.
42. Sorensen LF. Gout secondary to chromic renal disease: studies on urate metabolism. Ann Rheum Dis 1980;39:424-30.
43. McFarlane DG, Dieppe PA. Diuretic-induced gout in elderly women. Br J Rheumatol 1985;24:155-7.
44. Frocht A, Leek JC, Robbins DL. Gout and hyperuricemia in systemic lupus erythematosus. Br J Rheumtaol 1987;26:303-6.
45. Raman D, Abdalla AM, Haslock I. Coexistence rheumatoid arthritis and tophaceous gout: a case report. Ann Rheum Dis 1981;40:427-9.
46. Gordon TP, Ahern MJ, Reid C, Roberts-Thompson PJ. Studies on the interaction of rheumatoid factor with monosodium urate crystals and case report of coexistence tophaceous gout and rheumatoid arthritis. Ann Rheum Dis 1985;44:384-9.
Gouty arthritis by definition implies to a condition of joint inflammation due to the deposition of monosodium urat (MSU) crystal.1
Acute joint inflammation usually affecting the first metatarso-phalangeal joint referred to a very painful, redness and swollen joint that subsequently subsided within 5 to 10 days with or without medication. This condition recurred several times and between two acute episodes the patient beyond an intercritical phase. In other rare cases or chronic phase, several joints (polyarthritis) could be affected simultaneously.2,3 Recurrent attack and further deposition of MSU crystal will lead to a chronic condition and tophi develop.4,5,6 The deposition of tophi in the joint and bone will cause a serious damage to its structure and leading to deformities. Usually the development of tophi has a correlation with the severity of gout.
Epidemiology
The prevalence of hyperuricemia, gout and chronic tophaceous gout varies between countries.7 The WHO-ILAR-COPCORD stage I phase 3 researches in Bandungan, central Java, Indonesia, showed that the prevalence rate of gout and hyperuricemia in males 15 years of age and over is high compared to Caucasian populations. The prevalence of gout was 0.8% in the 4,683 people 15 years and older. Gout occurred in 1.7% of the men and 0.05% of the women. Acute gouty arthritis and chronic tophaceous gout were both found in the population sample.8 In Great Britain, the annual incidence rate (1971-1975), varying from 0.25 to 0.35 per 1000 and the prevalence of primary gout was estimated to be 2.3 per 1000.9 While in Taiwan the prevalence of gout was 0.60% in the rural area and 0.67% in the urban area.10 Another study from Indonesia, in northern part of Sulawesi indicating that chronic tophaceous gout was commonly seen among the population. Around 80% in the 208 population samples has developed tophi and various deformities.11 While in United State (USA) 35% in the 60 patients with gout also had tophi and deformities.12 A higher percentage compared to USA, 47% of 75 gouty arthritic patients in Thailand also developed tophi.13
Gouty arthritis was common in men rather than women. Previously, this disease was well known as the disease of King and the king of diseases. A bit different in sex differences founded in Polynesian women. Among them the differences to have hyperucicemia and gout was similar with those founded in men. This is to be believed caused by genetic defect in renal urate handling beside the occurrence of high purine intake and obesity.14
Factors affecting the formation of tophi
Hyperuricemia
A very high concentration of serum uric acid (SUA) always in correlation with the development of tophi. Tophus will be developed if the SUA level greater than 10 mg/dl. 4,5
The uric acid pool in patients with chronic tophaceous gout ranging between 18,000 – 31,000 mg. While in non tophaceous gouty arthritic patients the pool of uric acid is much lesser than the patients with tophus that is 2,400 – 3,600 mg. The uric acid pool was more than ten fold compared to normal person (1,200 mg). It is understandable why the patient with tophus will have an acute attack more frequent than those without tophus. This consideration derived from the fact that only a small amount of uric acid from the pool will be dissolved and excreted every day. 15
Genetic
A substantial part of gouty arthritic patients is a defect in purine metabolism, which is characterized by the increasing of purine synthesis, and it was abnormal. The acceleration of biosynthesis pointed to the genetic changes. Cassim B et al of Congella, South Africa founded that there was an increased in frequency of HLA-B14 in patients with primary gout but clinical significance of this is uncertain.16 The genetic defect resulting in disturbances of purine synthesis control mechanism.17 The most common abnormalities as a result in genetic changes were enzyme deficiency. It is Hypoxanthine guanine phosphoribocyl transferase (HPRT) as the main enzyme in regulating the purine synthesis. The HPRT deficiency will cause hyperuricemia.
The duration of having gouty arthritis
The development of tophus depends on the interval from the first attack of acute gout and it is lies between 3 – 42 years after the onset of gout. Becker and Levinson 4,5 found that tophus will be developed after 11.6 years of the onset of gout, while Nakayama et al 12 found the longer period around 18-19 years after. A few severe cases demonstrated that tophus already exist at the first acute attack of gout.18 This condition occur in a condition where the patient having renal problem, older age, on diuretic treatment and frequent use of non-steroidal anti-inflammatory drugs (NSAIDs). 19,20,21,22,23 Organ transplantation and the use of immunosuppressive agent such as cyslosporine-A was another factor for the formation of tophus at the first acute attack of gout.24
Obesity
Obesity was in correlation with the over production of uric acid and decreases of uric acid excretion. A low purine diet and weight loss program will improve the excretion of uric acid.1, 25,26 Dessein et al showed a beneficial effect of weight loss associated with moderate calorie / carbohydrate restriction (40%), and increases proportional intake of protein (30%) and fat (30%).27
Alcohol consumption
An alcoholic more prone to have gouty arthritis. The alcohol and its relationship with the incidence of gout could be arising from two different ways. The first, alcohol will increase the production of uric acid. Several kinds of alcohol beverages have a very high pure content. 28,29 The principle constituent found to be guanosine, which is probably the most readily absorbed dietary purine.30 Secondly, alcohol will decrease the excretion of uric acid.1,30 The second mechanism still on debatable. There is no evidence that beer taken in usual quantities will reduce the renal excretion of uric acid.30
In alcoholic gouty arthritic patients, the acute attack occurs in lower concentration of SUA in comparison to non-alcoholic gout patients.31
Purine intake
An abundant of purine consumption will lead to the overproduction of uric acid and at prolonged time will cause hyperuricemia uncontrollable and increasing the possibilities of deposition of uric acid crystal.1,4,5,32 Low purine diet will bring the SUA level to 15% lesser than normal diet.4
Dyslipidemia
Hypertriglyceridemia frequently found with gouty arthritis.4,33 Kelley and Wortman founded that lipid abnormalities among patients with gout was 75-84%.2 While Becker and Levinson founded hypertriglyceridemia in 50-75% of gouty arthritic patients.5
The mechanism of two differently metabolic abnormalities is not clearly understood. One study conducted by Moriwaki Y et al showed that there is a disturbance in apolipoprotein-e4 (apo-e4) allel.34 The apo-e is important in coating process of MSU crystal. The apo-e-coated MSU crystal will inhibit the inflammatory process in the synovium.
Renal function
Renal function is important in handling uric acid. Almost all of SUA will be filtrated in glomerulus and will be reabsorbed in renal tubule, so only a small amount of SUA will be excreted in the urine. Diminished renal function with the excretion less than 600 mg/dl a day will lead to hyperuricemia. It cannot compensate the production rate of SUA.1,4,32,35 This condition mostly has a genetic basis,36 and in the others there is the influences of drugs such as diuretics, pyrazinamide and ethambuthol. 37,38,39 Another factor should be in our mind that would be a major contributor of hyperuricemia and gout was the primary renal disease. 40,41,42,
Drugs
Many drugs could have its potentiality altering the renal function particularly in long-term therapy. The most common drug associated with the development of tophi was diuretic. A study on gout in Great Britain demonstrated that the elderly women are prone to diuretic-induced tophaceous gout but less likely to present with acute gout than man.43 Scott JT and Higgens CS founded that in diuretic induced gout there was one or more additional factors were present.23
Non-compliance to treatment
The invention of urate lowering drugs such as uricosuric agent or xanthine oxydase inhibitor (i.e allopurinol) is a remarkable inventory and brings the incidence of tophus down from 53% to 17%.5,24 In fact, many studies on gout still reported the high incidence of tophus. Nakayama et al 12 reported 35% of gout patients having tophus, and Louthrenoo reported a higher number, that is 47%.13 This condition is closely related to non-compliance to treatment.4,5,12,13
Other rheumatic disease associated with gout
The coincidence of other rheumatic disease with gout is well documented. In Systemic lupus erythematosus (SLE) the association of hyperuricemia and gout was closely associated with renal involvement particularly proteinuria and diuretic therapy.44 While in Rheumatoid arthritis (RA) the coexistence with gout is a questioned, more over with tophaceous gout. There is hypothesis that rheumatoid factor could inhibit the surface activity of monosodium urate crystals.46
Summary
Gout is a uric acid metabolism abnormality and known as one of the painful rheumatic disease. It has genetic basis. The chronic stage leading to joint and bone deformities known as chronic tophaceous gout. The incidence and prevalence of tophus varies between countries or from population to another within country. Hyperuricemia, renal function, non-compliance to treatment, alcohol consumption, obesity, hypertryglyceridemia, and duration of gout is a well-known risk factor for the development of tophus.
References
1. Emerson BT. Management of Gout. N Eng J Med 1996;334:445-51.
2. Perkins P, Jones AC. Gout. Ann Rheum Dis 1999;58:611-6.
3. Raddatz DA, Mahowald ML, Bilka PJ. Acute polyarticular gout. Ann Rheum Dis 1983;42:117-22.
4. Kelley WN, Wortman RL. Gout and hyperuricemia. In: Kelley WN, Harris ED, Ruddy S, Sledge CB eds. Textbook of Rheumatology 5th ed. WB Saunders Co. Philadelphia 1997;1313-51.
5. Becker MA, Levinson DJ. Clinical gout and the pathogenesis of hyperuricemia, In: Kopman WJ eds. Textbook of Rheumatology 13th ed. Williams and Wilkins. Baltimore 1997;2041-2101.
6. Tate G, Schumacher HR. Stages of gout. In: Schumacher HR, Klipel JH, Robinson DR, eds. Primer on the rheumatic disease 9th ed. Arthritis foundation. Atlanta GA 1998;195-206.
7. Darmawan J, Valkenburg HA, Muirden KD, Wigley RD. The epidemiology of gour and gyperuricemia in rural population of Java. J Rheumatol 1992; 1595-9.
8. Darmawan J. Rheumatic conditions in northern part of central Java. An epidemiological survey. MD Erasmus University Rotterdam, 1988;147-50 (thesis).
9. Currie WJ. Prevalence and incidence of the diagnosis of gout in Great Britain. Ann Rheum Dis 1979;38:101-6.
10. Chou CT, Pei L, Chang DM, Lee FC, Schumacher Jr HR, Liang MH. Prevalence of rheumatic disease in Taiwan: A population study of urban, suburban, rural differences. J Rheumatol 1994;21:302-6.
11. Padang C, Muirden KD, Schumacher HR. Chronic tophaceous gout in the northern part of Sulawesi. Proceeding of the eight APLAR Congress of Rheumatology. Melbourne 1996.
12. Nakayama DA, Bartheleny C, Carrera G, Lightfoot RW, Wortmann RL. Tophaceous gout: a clinical and radiographic assessment. Arthritis Rheum 1984;468-71.
13. Louthenoo W. Gouty arthritis in the northern part of Thailand. Proceeding of the third ASEAN Congress of Rheumatology, Bangkok, Thailand 1991.
14. Simmonds HA, McBride MB, Gatfield PJ, Graham R, McCaskey J, Jackson M. Polynesian women are also at risk for hyperuricemia and gout because of genetic defect in renal urate handling. Br J Rheumatol 1994;33:932-7.
15. Boss GR, Seegmiller JE. Hyperuricemia and gout. Classification, complication and management. N Eng J Med 300;26:1459-68
16. Cassim B, Mody GM, Deenadayalu VK, Hammond MG. Gout in black South Africans: a clinical and genetic study. Ann Rheum Dis 1994;53:759-62.
17. Kelley WN, Greene ML, Rosenbloom FW et al. Hypoxanthine-guanine phosphoribocyl transferase deficiency in gout. Ann Int Med 1969;70:155-94.
18. Wernick R, Winkler C, Campbell S. Tophi as the initial manifestation of gout. Arch Int Med 1992;152:873-6.
19. Pulg JG, Michan AD, Jimenez ML et al. Female gout. Clinical spectrum and uric acid metabolism. Arch Int Med 1991; 151:726-32.
20. Lally EV, Hogh JR, Kaplan SR. The clinical spectrum of gouty arthritis in women. Arch Int Med 1986;146:2221-5
21. Simkin PA, Campbell PM, Larson EB. Gout in Heberdens Nodes. Arthritis Rheum 1983;26:94-7
22. Mc Farlane DG, Dieppe PA. Diuretic induced gout in elderly woman. Br J Rheumatol 1985;155-7.
23. Scott TJ, Higgens CS. Diuretic induced gout: A multifactorial condition. Ann Rheum Dis 1992;259-61.
24. Roubenoff R, Klag MJ, Mead LA et al. Incidence and risk factors for gout in white man. JAMA 1991;304-7.
25. Emmerson BT. Alteration of urate metabolism by weight reduction. Aust NZ J Med 1973;410-2.
26. Faller J, Fox JH. Ethanol induced hyperuricemia: Evidence for increased urate production by activation of adenine nucleotide turn over. N Eng J Med 1982; 1598-602.
27. Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie / carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoproteion levels in gout: a pilot study. Ann Rheum Dis 2000;59:539-43.
28. Eastmond CJ, Garton M, Robins S, Riddoch S. The effects of alcoholic beverages on urate metabobilsm in gout sufferes. Br J Rheumatol 1995;34:756-9.
29. Gibson T, Rodgers AV, Simmonds HA, Court-Brown F, Todd E, Meilton V. A controlled study of diet in patients with gout. Ann Rheum Dis 1983;42:123-7.
30. Gibson I, Rodgers AV, Simmonds HA, Toseland P. Beer drinking and its effect on uric acid. Br J Rheumatol 1984;203-9.
31. Vandenberg MK, Moxley G, Breitbach SA, Roberts WN. Gout attacks in chronic alcoholic occur at lower serum level than in non alcoholic. J Rheumatol 1994;700-4.
32. Maclachlan MJ, Rodman GP. Effect of food, fat and alcohol on serum uric acid and acute attack of gout. Am J Med 1967;38-57.
33. Holmes EW, Kelley WN, Wyngaarden JB. The kidney and uric acid excretion in man. Kidney Int 1972;115-8.
34. Moriwaki Y, Yamamoto T, Takahashi S, Tsutsumi Z, Higashino K. Apolipoprotein E phenotypes in patients with gout: relation with hypertriglyceridaemia. Ann Rheum Dis 1995;54:351-4.
35. Grayzel AL, Liddle I, Seegmiller JE. Diagnostic significance of hyperuricemia in arthritis. N Eng J Med 1961;763-8.
36. Postlewaite AE, Bartel AG, Kelley WN. Hyperuricemia due to ethambutol. N Eng J Med 1972;761-2.
37. Star VL, Hochberg MC. Gout: Prevention and management. Medical Progress 1984;47-52.
38. Sew Hoy MD. Gout: Common sense management. Mediacal progress 1991;47-52.
39. Bull PW, Scott JT. Intermittent control of hyperuricemia in the treatment of gout. J Rheumatol 1989;1246-8.
40. Vecchio PC, Emmerson BT. Gout due to renal disease. Br J Rheumatol 1992;31:63-65.
41. Gibson T, Waterworth R, Hatfield P, Robinson G, Bremner K. Hyperuricaemia, gout and kidney function in New Zealand Maori Men. Br J Rheumatol 1984;23:276-82.
42. Sorensen LF. Gout secondary to chromic renal disease: studies on urate metabolism. Ann Rheum Dis 1980;39:424-30.
43. McFarlane DG, Dieppe PA. Diuretic-induced gout in elderly women. Br J Rheumatol 1985;24:155-7.
44. Frocht A, Leek JC, Robbins DL. Gout and hyperuricemia in systemic lupus erythematosus. Br J Rheumtaol 1987;26:303-6.
45. Raman D, Abdalla AM, Haslock I. Coexistence rheumatoid arthritis and tophaceous gout: a case report. Ann Rheum Dis 1981;40:427-9.
46. Gordon TP, Ahern MJ, Reid C, Roberts-Thompson PJ. Studies on the interaction of rheumatoid factor with monosodium urate crystals and case report of coexistence tophaceous gout and rheumatoid arthritis. Ann Rheum Dis 1985;44:384-9.
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