HLA B27

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HLA B27

Post by Mike Bartolatz » Thu Dec 01, 2005 6:37 pm

Etiopathogenic role of HLA-B27 alleles in ankylosing spondylitis
Authors: AKKOC, Nurullah1; KHAN, Muhammad Asim2

Source: APLAR Journal of Rheumatology, Volume 8, Number 3, December 2005, pp. 146-153(8)

Publisher: Blackwell Publishing

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Abstract:


HLA-B27 is the major genetic susceptibility factor for ankylosing spondylitis (AS). However, its precise role in the pathogenesis of AS still remains unclear, even though its gene has been cloned and sequenced, and its crystallographic structure has been defined. Arthritogenic peptide and molecular mimicry hypotheses propose mechanisms related to an antigen-presenting function of HLA-B27 to be responsible for disease development. However, peculiar aspects of its immunobiology, such as its misfolding and heavy chain dimerization raise the possibility of involvement of pathogenic mechanisms unrelated to its physiological function. Moreover, HLA-B27 is not a single allele, but a family of 31 different alleles, named HLA-B*2701 to HLA-B*2727. Studies worldwide indicate that the relatively common alleles (subtypes) HLA-B*2705, B*2704, and B*2702 are strongly associated with AS, whereas HLA-B*2706 which is prevalent in South-east Asia and HLA-B*2709 which is prevalent on the Italian island of Sardinia, seem to lack such an association. The distinction between the disease-associated subtypes and those that are not associated, may provide clues to the actual role of HLA-B27 in disease pathogenesis. B*2706 differs from B*2704 by only two residues, and B*2709 differs from B*2705 by only one residue. Moreover, both B*2706 and B*2709 bind an endogenous peptide (derived from vasoactive intestinal peptide type 1 receptor) and also an exogenous peptide (latent membrane protein 2 of Epstein-Barr virus) but in two drastically diverse conformations. These recent X-ray diffraction studies of individual peptides in the context of different HLA-B27 alleles broaden our perception of the possible pathogenetic role of this molecule in the development of AS and related spondyloarthopathies. In summary, the pathogenetic role of HLA-B27 in AS seem to be quite heterogenous, and cannot be explained by a single mechanism, and new ideas have been raised based on the aberrant immunobiologic features of HLA-B27.
Keywords: alleles; ankylosing spondylitis; etiopathogenesis; genetics; HLA-B27; polymorphisms; spondyloarthropathies; subtypes

Document Type: Special article

DOI: 10.1111/j.1479-8077.2005.00152.x

Affiliations: 1: Division of Rheumatology and Immunology, Department of Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey 2: Case Western Reserve University School of Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA

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Last edited by Mike Bartolatz on Sat Dec 03, 2005 3:32 pm, edited 1 time in total.
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HLA B27 in Asian Populations

Post by Mike Bartolatz » Thu Dec 01, 2005 6:40 pm

HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations.

Lopez-Larrea C, Sujirachato K, Mehra NK, Chiewsilp P, Isarangkura D, Kanga U, Dominguez O, Coto E, Pena M, Setien F, et al.

Hospital Central de Asturias, Oviedo, Spain.

The aim of this study was to investigate the contribution of the different B27 subtypes to ankylosing spondylitis (AS) susceptibility. The polymerase chain reaction (PCR) in combination with the sequence-specific oligonucleotide probes (SSOs) was used to analyse the polymorphism in exon 2 and 3 of HLA-B27 in two Asian groups with different genetic HLA structures: Indian (I) and Thai (T) populations. The same number of AS patients (45) and healthy B27 positive donors (n = 17) from both populations were analysed in order to ascertain the B27 subtypes. Three different findings can be concluded from this study: 1) B*2707 has been found to be associated with AS in both populations. This association has not been previously reported in either ethnic group. 2) B*2704 is strongly associated with AS in the Thai patients (91% in AS vs. 47% in C; RR = 11.5; EF = 0.83). In contrast, B*2704 was found with similar frequency in Asian Indians AS patients and controls (41% in AS vs. 41% in C.). 3) B*2706 was found overrepresented in control populations and absent in AS patients (0% in AS vs. 47% in C.; pc < 10(-6)) showing the maximum value of protective fraction (PF = 1). The B*2706 negative association with AS has not been previously described in other ethnic groups and could indicate a protective effect of this subtype on AS susceptibility. The B*2706 allele has two changes relative to B*2704 at residue 114 (His to Asp) and 116 (Asp to Tyr) in the pockets D/E. The importance that these differences can play in the pathogenesis of AS are discussed.

PMID: 7761976 [PubMed - indexed for MEDLINE]
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HLA B27 in India

Post by Mike Bartolatz » Thu Dec 01, 2005 6:46 pm

HLA-B27 allele diversity in Indians: impact of ethnic origin and the caste system
British Journal of Biomedical Science, 2003 by Shankarkumar, U

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ABSTRACT

HLA-B27 is a serological specificity which encompasses an increasing number of subtypes that show varied racial/ethnic prevalence in the world. Here, data from 5129 Indians (4500 population and caste; 629 tribal) is compiled from the literature. In addition, HLA-B27 subtyping of 58 positive individuals from Maharastra is presented. Analysis revealed an increased B27 antigen frequency among the north Indian groups (>5%) compared to the south Indian groups (

KEY WORDS: Alleles.

Ethnic groups.

HLA-B27 antigen.

Social class.

Introduction

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HLA-B27 shows a remarkable association with ankylosing spondylitis (AS) and related seronegative spondarthropathies (SSA), and plays a direct role in disease pathogenesis.1 It is a serological specificity that encompasses an increasing number of alleles (subtypes) which show varied racial/ethnic prevalence in the world.2

HLA-B27 represents a family of 25 closely related alleles (B*2701-B*2725).3 These subtypes differ by one or more amino acid substitutions in the antigenic peptide-binding groove.4 The Indian population is well known for its genetic diversity, and distributions of HLA antigens among regional Indian populations are available;5-22 however, data from indigenous caste and tribal groups are limited.23-26

The present study aims to identify the HLA-B27 antigen frequencies among different Indian caste/tribal population groups reported in the literature, and to identify the subtypes among 58 B27-positive individuals belonging to different caste and tribal groups from western India.

Materials and methods

Data from 5129 Indians (population/caste 4500; tribes 629) were compiled for their HLA-B27 antigen frequency distribution based on the regional, caste and tribal distribution. Molecular subtypes in the 58 B27-positive individuals identified from a cohort of 1129 normal healthy individuals belonging to different caste and tribal groups from Maharastra were initially carried out by serological methods.27

Details of the caste and tribal groups are described elsewhere.28 DNA extracted from the 58 B27-seropositive individuals was then confirmed by polymerase chain reaction (PCR)-based sequence-specific primer (PCR-SSP) analysis using a commercial kit (BAG histotype DNA-B27, Germany). The subtypes were genotyped using a reverse line strip sequence-specific oligo nucleotides probe (RLSSSOP) hybridisation kit (Roche Molecular, Oakland, CA). Phenotype and genotype frequencies were estimated using standard methods.

Results

B27 antigen frequency distribution among the Indian population, caste groups and tribal groups are presented in Table 1. Comparative results showed an increased prevalence of the HLA-B27 allele among north Indian caste/population groups (2.7-29%) over the south Indian caste/population groups (0.9-2.1%).

Christian (an amalgamation of different caste groups) and Lucknow populations showed increased B27 frequency; whereas, the B27 allele was not identified among the tribal groups in the Malayali and Irula tribes from south India. Tribal groups are more isolated than caste groups because their population distribution is restricted to the hill regions; thus, their HLA-B27 allele frequencies were increased (2.6-8.6%) when compared to the caste and population groups. Furthermore, western Indian caste/population groups from the Maharashtra and Gujarat states showed a different B27 frequency (1.4-15%).

Subtypes among the selected caste and tribal groups from western India (Table 2) included B*2704, B*2705, B*2707, B*2708 and B*2714. HLA B*2704 and B*2705 subtypes were found in most of the caste and tribal groups, while B*2708, B*2707 and B*2714 showed a restricted distribution among the selected caste or tribal groups studied.

Discussion

It is well established that HLA-B27 subtypes differ in their ethnic distribution, perhaps as a result of genetic and geographical origin; however, the B*2705 subtype is present in almost all the populations studied worldwide, and is over-represented in the circumpolar and subartic regions of Eurasia and North America.

In contrast, B*2704 is virtually restricted to Oriental and Polynesian populations. B*2707 has been detected in Asian populations.30,31 B*2708, which is a rare subtype, has been identified in those from the Azores, Britain and in western Indians32,33 of the Jains, Maratha and Gujarathi caste groups. B*2714, a recently identified subtype, has been reported in North American Indians, Siberians, western Indians33 and among those of the Kunbi caste in India.

Amino acid variation among subtypes and their distribution in world populations strongly suggest that B*2705 could be the ancestral B27 subtype from which all others have evolved, possibly by genetic mechanisms of reciprocal recombination, point mutation or antigen-driven gene conversion.34 Furthermore, the HLA-B27 allere has also been associated with patients with haemophilia and chronic synovitis.35

Population-specific distribution of HLA alleles is necessary both in population genetics and in HLA disease association studies.36 Anthropological studies show that the distribution of HLA alleles differs from one ethnic group to another, and new alleles may yet be discovered in the Indian population.37 The various Indian caste groups differ in their origin, migration and settlement, although they have embraced Hinduism since ancient times.

Analysis of genetic data suggests that the inhabitants of the western part of the Eurasian Steppes, originally settled by Caucasoid people speaking Indo-European languages, migrated in various directions, including towards Iran and India. It is believed that these pastoral nomads often formed hierarchical societies and introduced the caste system to the Indian subcontinent.38

Migration has a linear effect on HLA-B27 antigen frequency and Neolithic demie diffusion, and could be the cause of nationwide genetic gradients. Thus, more extensive typing of the Indian population will be necessary to resolve the evolutionary implications of HLA-B27 subtypes and their population demography and relative disease association in the Indian context.

The author would like to thank Dr J V Undevia, Professor S.Chokalingam, Professor TJ Pandian and Professor R M Pitchappan for their support and encouragement during the preparation of this manuscript.

References

1 Khan MA. Spondyloarthropathies. In: Hunder G, ed. Atlas of rheumatology. Philadelphia: Current Science, 1998: 5.1-5.24.

2 Khan MA. HLA B27 and its subtype in world population. Curr Opin Rheumatol 1995; 7: 263-9.

3 Marsh SGE, Albert ED, Bodmer WF et al. Nomenclature for factors of HLA system 2002. Hum Immunol 2002; 63: 1213-68.

4 Lopez-Larrea C, Gonzaley S, Martinez-Borra J. The role of HLA B27 polymorphism and molecular mimicry in spondyarthropathy. MoI Med Today 1998; 4: 540-9.

5 Mittal KK, Naik S, Sansonetti N, Cowherd R, Kumar R, Wong DM. The HLA antigens in Indian Hindus. Tissue Antigens 1982; 20: 223-6.

6 Hammond MG, Asmal AC. HLA and insulin-dependent diabetes in South African Indians. Tissue Antigens 1980; 15: 244-8.

7 Selvakumar A, Damodaran C, Chandrasekaran E Distribution of HLA antigens in native South Indian Tamil Hindus. Tissue Antigens 1988; 31: 136-40.

8 Pitchappan RM, Kakkanaiah VN, Rajasekar R, Arulraj N, Muthukkaruppan VR. HLA antigens in South India: I. Major groups of Tamil Nadu. Tissue Antigens 1984; 24: 190-6.

9 Subramanian VS, Selvaraj P, Narayanan PR, Prabhakar R, Damodaran C. Distribution of HLA (Class I and Class II) antigens in the native Dravidian Hindus of Tamil Nadu, South India. Gene Geography 1995; 9: 15-24.

10 Mehra NK, Taneja V, Kailash S, Raizada N, Vaidya MC. Distribution of HLA antigens in a sample of the North Indian Hindu population. Tissue Antigens 1986; 27: 64-74.

11 Rajalingam R, Mehra NK, Mehra RD, Neolia S, Jain RC, Pande JL. HLA class I profile in Asian Indian patients with pulmonary tuberculosis. Indian J Exp BM 1997; 35: 1055-9.

12 Papiha SS, Wentzel J, Shah KC, Roberts DF. HLA antigens in the three population of India. Hum Hered 1989; 39: 136-40.

13 Shankarkumar U, Pednakar SV, Gupte S, Ghosh K, Mohanty D. HLA antigen distribution in Marathi-speaking Hindu population from Mumbai, Maharastra, India. J Hum Ecol 1999;10: 367-72.

14 Chayya SU, Panthaki M, Shankarkumar U. HLA antigen distribution in Gujarathi- speaking Hindu population from Mumbai, Maharastra, India. Anthropologist. 2000; 2: 7-12.

15 Chayya SU, Shankarkumar U. HLA antigen distribution in Jain community from Mumbai, Maharastra, India. Indian J Med Res 2001; 114: 25-9.

16 Shankarkumar U. Ghosh K, Colah RB, Gorakshakar AC, Gupte SC, Mohanty D. HLA antigen distribution in selected caste groups from Mumbai, Maharastra, India. J Hum Ecol 2002; 13: 209-15.

17 Rajasekar R, Kakkanaiah VN, Pitchappan RM. HLA antigens in South India: II. Selected caste groups of Tamil Nadu. Tissue Antigens 1987; 30: 113-8.

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HLA B27 worldwide

Post by Mike Bartolatz » Thu Dec 01, 2005 6:54 pm

HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis.

Gonzalez-Roces S, Alvarez MV, Gonzalez S, Dieye A, Makni H, Woodfield DG, Housan L, Konenkov V, Abbadi MC, Grunnet N, Coto E, Lopez-Larrea C.

Department of Immunology, Hospital Central de Asturias, Oviedo, Spain.

HLA-B27 is strongly associated to ankylosing spondylitis (AS) and represents a family of eleven B27 alleles (B*2701-11). Our aim was to analyze the distribution of B27 subtypes by PCR/SSOP and genomic sequencing in a large group of populations (n = 17). 711 B27-positive samples from Caucasoid, Asian, African, Amerindian and Polynesian populations were selected to ascertain transracial gene mapping of the B27 subtypes. 476 of these were AS patients, chosen to investigate the contribution of B27 alleles to AS susceptibility. Some significant new findings have arisen from this study: 1) B*2705 was the predominant subtype in circumpolar and subarctic areas. B*2702 was found to be practically restricted to Caucasian populations, showing a higher frequency in Middle-East (Jews) and North Africa (Arabs/Berbers) groups. 2) B*2703 appears associated with AS in Western Africans. This is of remarkable interest since it was suggested that B*2703 would be negatively disease-associated. 3) Although B*2706 appears negatively associated with AS in Thais, we identified two patients from northern China carrying it. This may be a reflection of a disease heterogeneity and could indicate that more than one pathogenic agent can be involved in AS. B*2709 has been recently described as negatively associated with AS in Sardinians. The molecular changes His114Asp (B*2706) and Asp116His (B*2709) could modify the genetic susceptibility to AS.

PMID: 9062966 [PubMed - indexed for MEDLINE]

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Spondyloarthropathies

Post by Mike Bartolatz » Thu Dec 01, 2005 7:07 pm

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HomeIntroductionTypes of spondyloarthropathiesHLA B27 antigenTable II. HLA B27 and the SpondyloarthropathiesAnkylosing spondylitisPsoriatic arthritisReiter's syndromeOther types of spondyloarthropathiesResources
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Continuing Medical Education: Spondyloarthropathies. University of Washington, Seattle
Edited By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

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Introduction
Types of spondyloarthropathies

The spondyloarthropathies are a heterogeneous set of disorders characterized by axial skeletal involvement and an association with the HLA B27 antigen. Listed below are the entities included in this group of disorders.

Ankylosing spondylitis
Juvenile ankylosing spondylitis
Late onset spondyloarthropathy
Psoriatic arthritis
Reiter's syndrome/reactive arthropathy
Enteropathic spondylitis
Undifferentiated spondyloarthropathy
HLA B27 antigen

The association with the HLA B27 antigen has had a significant impact on our understanding of these diseases. The HLA B27 antigen is a so-called class 1 major histocompatibility complex product whose gene is located on the short arm of the sixth chromosome. The antigen consists of two chains; an alpha chain made by the gene on the sixth chromosome, and a B2 microglobulin molecule whose gene is located elsewhere and stabilizes the alpha chain. All nucleated cells and platelets contain class 1 molecules. These antigens are important in the recognition of self by cytotoxic T cells and participate in immunity to viral infection and also are important in transplantation rejection. In 1973, it was first recognized that the HLA B27 antigen was associated with a susceptibility to ankylosing spondylitis. Since then association with other spondyloarthropathies has been elucidated. Below is the relative percentages of HLA B27 in patients with these diseases.
Table II. HLA B27 and the Spondyloarthropathies

Spondyloarthropathy Degree of Association
Ankylosing spondylitis > 90%
Reiter's/reactive arthritis > 80%
Enteropathic spondylitis 75%
Psoriatic spondylitis 50%


Normal Population

Caucasian 8%
African Americans 4%
Native Americans 13%

At least one family study suggests that up to 25% of HLA B27 positive relatives of patients with ankylosing spondylitis may have signs and symptoms of inflammatory back pain but do not meet full criteria for ankylosing spondylitis. The utility in ascertaining the B27 haplotype in individuals with inflammatory back symptoms is that it might be an impetus to proceed with further evaluation or try second line anti-inflammatory medications in equivocal cases.

Another important association of the HLA B27 antigen, not listed above, is in men with lone aortic incompetence in combination with pacemaker requiring bradycardia.

Recently, the HLA B27 gene was introduced into rats so that there is now an animal model to study these diseases.




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Spondyloarthropathies

Post by Mike Bartolatz » Thu Dec 01, 2005 7:08 pm

Our Surgeons & Faculty « All Articles
Continuing Medical Education: Spondyloarthropathies. University of Washington, Seattle
Edited By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

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Ankylosing spondylitis
What is AS?

Ankylosing spondylitis (AS) is the prototypic spondyloarthropathy. The term comes from the Greek ankylos (bent or crooked) and spondylos (vertebra). There is evidence of AS in ancient Egypt as far back as 2900 B.C. The prevalence in the U.S. population in between 0.5 and 1.0 percent. The prevalence figures for certain Native Americans are as high as 18-50 percent. The sex ratios are almost equal but the disease is more often clinically apparent in males. The usual age of onset for AS is between the second and fourth decade of life.
Pathology

If rheumatoid arthritis is thought of as a disease of the synovium then AS is a disease of the enthesis which is the site where ligaments, tendons, and joint capsules insert into bone. At these sites, inflammation occurs leading to fibrosis and ossification. These changes have a predilection for the enthesis about vertebrae, facet joints, and feet. Inflammation is followed by fibrosis which is followed by ossification leading to the ankylosis so characteristic of this disorder.
Clinical features

Axial Skeleton
The symptoms of AS are typically insidious in nature. Patients complain of morning low back stiffness lasting 30 minutes to several hours. Pain and stiffness at night and with prolonged sitting is also characteristic. The discomfort is felt in the low back and buttock area and is improved with exercise. If the disease progresses, immobility occurs due to fibrosis and ossification of enthesis about the spine. The entire spine may be affected and in severe cases, patients may develop the so called "bamboo spine". The insertions of the ribs into the spine and intercostal enthesis can also be affected leading to pleuritic-like chest pain with deep breathing and with time fibrosis of these attachments may cause decreased inspiratory excursion of the chest. Sacroiliac joints are usually involved symmetrically but one side may be more involved than another. Sternoclavicular and tempromandibular joints can also be affected.

Spinal mobility can be measured by the Schober test done by drawing a 10 cm line up from the midposterior iliac spines (the "dimples"). Have the patient bend forward and measure the distraction. Normal is greater than five cm.

Peripheral Joints
AS can also affect the peripheral joints in particular the hips, the shoulders, and the ankles. Overall, 35 percent of patients may have peripheral joint manifestations. This is said to occur more frequently in females. Peripheral joint disease is usually asymmetric.

Enthesopathy
The Achilles tendon and the plantar fascia are frequently affected causing considerable discomfort. The Achilles tendon may be quite swollen and tenderness and is usually at the insertion into the calcaneous. Dactylitis (diffuse swelling of the fingers or toes also called sausage digits) may also be present representing diffuse enthopathy.

Eye Disease
As many as 25 percent of patients with AS may have this manifestation during the course of their illness. Anterior uveitis or iritis is typically episodic and unilateral. Blindness is rare but the uveitis may be severe enough to require local or even systemic corticosteroids. Eye involvement appears to be more common in patients with peripheral joint disease.

Cardiovascular Disease
This complication usually occurs in patient with long standing severe AS with peripheral joint involvement. Aortic incompetence may be a combination of aortic valve cusp fibrosis and or aortitis distal to the valve itself. Complete atrioventricular block with Stokes-Adams attacks may occur. Cardiac involvement is found in up to 10 percent of patients after 10 years of disease.

Pulmonary Disease
Patients with severe spondylitis may develop upper lobe fibrosis. Cysts formation may occur and these may be colonized by Aspergillus. Patients may succumb to massive hemoptysis. Restrictive lung disease may be present but is normally mild.

Important Spinal Complications
The immobile spine fractures easily with even minor trauma. The most common site is the cervical spine. Most fractures center around C5 and are transverse through the disc space. Gross instability can occur leading to impingement on the cord or vertebral arteries. Fracture may not be apparent on X-ray and may require CT scan or bone scan to localize. This is a true rheumatologic urgency.

The cauda equina syndrome may cause insidious onset of pain in the buttocks or legs associated with bowel and bladder symptoms. This is due to spinal cord compression at the level of the cauda equina. Myelogram or MRI demonstrate lumbar diverticuli. Therapy, including surgery and high dose steroids, have not been satisfactory.

Spinal stenosis can also occur due to bone over growth and nerve impingement. This may respond favorably to surgery.

Spondylodiscitis occurs at a vertebral disc space (usually in the thoracic spine) that has become mobile. It is a source of mechanical-type back pain and although not usually unstable, can be a source of significant pain. On X-ray, there is usually erosion of the vertebral end plates and may mimic an infectious process. Treatment is by surgical fusion or trial of bracing to allow the segment to refuse on its own.

Radiographic features

Sacroilitis
Initial changes include blurring of the joint margins and reactive sclerosis. With progression there may be complete fusion of the joints. Bilateral sacroilitis occurs in AS. Early changes at the sacroiliac joints are nicely demonstrated by CT scan.

Syndesmophytes
These occur from ossification of the area of the annulus fibrosus and bridge adjacent vertebrae. With advancing disease, these can give the spine a bamboo appearance.

Vertebral Squaring
Erosions at the vertebrae occur first at the anterosuperior anteroinferior corners. This leads to the appearance of squaring.

Reactive Sclerosis
The anterior edges of the vertebrae can develop reactive sclerosis and have a so-called "shining corner" appearance. Reactive sclerosis/"fluffy" periostitis can also develop at the symphysis pubis and the ischium.

Calcaneal Spurs/Erosions
Erosions can develop around the Achilles tendon insertion and calcaneal spurs are also common. Periostitis can occur at the calcaneus giving a "fluffy" appearance to the heel.

Treatment

Education
Patients need to know the nature of their illness and its treatment. An extensive discussion is important for those who are recently diagnosed. There are educational materials available through the Arthritis Foundation, the Spondylitis Association of America, and on this web site.

Physical Therapy
All patients should be sent to see a physical therapist when diagnosed to learn techniques for good posture and daily stretching. Patients should be encouraged to stay active! Swimming is an excellent activity for patients with arthritis.

Medication
NSAIDs are the mainstay of treatment. Patients usually have very immediate relief. Indomethicin or phenylbutazone (now under restricted use) are felt to be the most effective but most NSAIDs will work. Patients on these medication long term need to be monitored on a regular schedule (at one month then every three to twelve months thereafter).
Corticosteroids are useful for intra-articular use for peripheral joints but are not felt to be effective for spinal disease.
Sulfasalizine has recently been found useful for both the peripheral joint involvement but also shows promise in the spinal disease as well.
Other medications: Methotrexate is used by many rheumatologists but there are few studies. Of historic interest is the use of radiation which apparently did wonders for the spinal disease but lead to high a incidence of leukemia.
Surgery
There is a limited role for surgery except in patients with severe hip or shoulder disease. A neurosurgeon or orthopaedic spine surgeon should be consulted early for spine fractures, cauda equina syndrome or spondylodiscitis.

Prognosis

The prognosis is dfficult to assess but overall the disease is less severe in women. Most patients have a good prognosis with a minority progressing to significant disability as was seen in the past. There is about a 10-20% risk for offspring of developing the disease. The key may be early diagnosis and institution of NSAIDs to reduce pain and mobility exercises to prevent fusion.


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psoriatic arthritis

Post by Mike Bartolatz » Thu Dec 01, 2005 7:09 pm

Home « Our Surgeons & Faculty « All Articles
Continuing Medical Education: Spondyloarthropathies. University of Washington, Seattle
Edited By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

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Psoriatic arthritis
About psoriatic arthritis

The association of psoriasis with arthritis was first made by the French in the early 19th century. Approximately six percent of people with psoriasis develop arthritis. The joint disease of psoriasis needs to be separated into the peripheral joint disease, which is not associated with B27 but rather HLA-B38 and B39, and psoriatic spondylitis which is associated with the B27 antigen. The male:female ratio in psoriatic arthritis is 1:1. Remember that widespread psoriasis may not be present and may be confined to the scalp, umbilicus, or natal cleft as the only location. Skin and joints may flare concurrently in some patients.
Clinical subgroups

There are five patterns of joint disease in psoriatic arthritis and are listed below. One pattern can evolve into another.

Asymmetric oligoarthritis
This is the most common type and occurs in over one half of the patients with psoriatic arthritis. The DIPs PIPs of the hands and feet as well as the MTPs are frequently involved. In addition, the knees, hips, ankles, and wrists are commonly affected. A common finding is the whole digit to be swollen when the tendon sheath is involved and this gives the digit a sausage appearance.

DIP Arthritis
This is a less common form and makes up five to ten percent of patients with psoriatic arthritis. The DIP joints are affected in a oligoarticular pattern in association with classic nail changes of psoriasis (pitting, hyperkeratosis, separation of the subungual bed).

Arthritis Mutilans
This typically occurs in patients with wide spread severe psoriasis and there is often a spondylitis present. The affected digitis undergo significant osteolysis leading to so called "opera glass deformities."

Symmetric Polyarthritis
This form has a pattern similar to rheumatoid arthritis but usually with less deforming disease. One characteristic is fusion of the wrist which does not typically occur in rheumatoid arthritis.

Psoriatic Spondylitis
Twenty to 40 percent of patients with psoriatic arthritis may have some degree of sacroilitis often asymptomatic. The spondylitis is typically more asymmetric than with AS with paravertebral ossification between the vertebrae rather than syndesmophytes.

Radiographic features

Reactive Periostitis
This "fluffy" appearing bony change at the enthesis is a hallmark for all of the spondyloarthropathies. Enthesitis occurs in psoriatic arthritis just as in AS with similar locations. In addition, reactive bony changes occur in the peripheral joints in association with erosions.

Marginal Erosions
These occur in similar fashion to rheumatoid arthritis but the distribution of the involved joints along with the reactive bone changes help to distinguish it form rheumatoid arthritis. A characteristic lesion is the "pencil in a cup" deformity at the interphalangeal joints of the digits.

Sacroilitis
As discussed above, it may be less symmetric in nature than AS.

Paravertebral Ossification
Also called non-marginal syndesmophytes. These can be seen in the absence of sacroilitis and may be more asymmetric and sporadic than the syndesmophytes of AS.

Treatment

NSAIDs
These are the mainstay of treatment but be aware that shunting of arachidonic acid to the lipoxygenase pathway may lead to a flare of the skin disease.

Corticosteroids
Very useful for the peripheral joint disease. Both low dose orally or intra-articular corticosteroids in a fashion similar to rheumatoid arthritis can be used. The skin may also be benefited from oral corticosteroids.

Antimalarials (hydroxychloroquine, chloroquine)
These agents have been used successfully for treatment of the peripheral joint disease but also may flare the skin especially chloroquine.

Gold Compounds
Both oral and IM gold are effective in treating the peripheral joint disease. Given in a similar fashion to rheumatoid arthritis.

Sulfasalazine
This agent has been shown to be effective in a variety of inflammatory forms of arthritis. Beneficial for both the peripheral and axial involvement.

Methotrexate
Methotrexate has been in use for psoriasis for many years and is one agent that can treat skin, peripheral joint, and axial skeletal involvement. Dosed as per rheumatoid arthritis one time per week.

Miscellaneous
Cyclosporin, PUVA, etretinate, azathioprine, have all been reported useful in small groups of patients.




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Reiter's syndrome

Post by Mike Bartolatz » Thu Dec 01, 2005 7:10 pm

By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

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Reiter's syndrome
History

This disorder takes its name from Professor Hans Reiter who is given credit for first describing the features of the disease that bears his name in a young officer in the Prussian army. Classically, the disease has been defined by the triad of arthritis, conjunctivitis, and urethritis. More recently the disease has been defined more broadly.
Definition

The present criteria for defining Reiter's syndrome are listed below.

Table III. Definition of Reiter's Disease*

Seronegative asymmetric arthritis
PLUS one or more of the following: Urethritis/cervicitis
Dysentery
Inflammatory eye disease
Mucocutaneous disease

Exclusions include: Ankylosing spondylitis
Psoriatic arthritis
Other rheumatic diseases

* Adopted from Calin A: Textbook of Rheumatology, 3rd Edition, W. B. Saunders Co.

Reiter's syndrome affects men more often than women with the ratio of about 5:1. It can occur at any age but is principally seen among the 20 to 30 year old age group.

Reiter's syndrome has also been termed a reactive arthritis because it appears to be closely linked to various infectious agents. The notion has been that there is a molecular mimicry between antigens on the organism and the enthesis of the HLA B27 positive host leading to inflammation directed against the host as well as the organism. More recently, some investigators have felt that they have been able to identify chlamydia like organism in patients with Reiter' disease/reactive arthritis suggesting persistent synovial presence of organisms thought responsible for this disorder. Below is listed the agents presently recognized to be associated with Reiter's syndrome. The manifestations of Reiter's disease typically begin two to six weeks after such an infection.

Recently it has been recognized that Reiter's syndrome/psoriatic arthritis occur with an increased frequency in patients with HIV infection. This may be due to the various enteric infections that occur or to CD8 T cell activity.

Table IV. Organisms Associated with Reiter's Syndrome

Postdysentery Postvenereal
Shigella Chlamydia
Salmonella Mycoplasma
Yersenia
Campylobacter

Clinical features

Peripheral Arthritis
The pattern seen with Reiter's syndrome is characteristically an asymmetric pauciarticular or polyarticular arthritis predominantly affecting the lower extremities. These patients may have very large effusions. "Sausage digits" may be seen at the fingers or toes similar to those in the other spondyloarthropathies.

Axial Arthritis
Patients may complain of low back pain during the course of an attack but development of spondylitis usually occurs in patients with long standing persistent disease.

Enthesitis
Similar in location to other spondyloarthropathies. Patients may have significant swelling of the Achilles tendons and the involvement at this location has been termed in the past "lovers heel" due to the association with venereal disease.

Eye Disease
Conjunctivitis is the most common manifestation at the eye and may go unnoticed by the patient. Uveitis may occur and can be more serious than that seen in AS. Iridocyclitis and even optic neuritis have been described in Reiter's syndrome.

Urogenital Disease
The urethritis seen in Reiter's can occur from postvenereal infection but also after infection from the enteric organisms. This has raised the question of the mechanism of urethritis in Reiter's syndrome. Prostatitis may occur in some degree in up to 80% of patients.

Mucocutaneous Disease
There are several characteristic lesions that occur in Reiter's disease. Keratodermia blennorrhagicum occurs typically on the soles but may be seen on the palms, scalp, trunk, or scrotum. They begin as vesicles the form hyperkeratotic plaques that coalesce. Microscopically they are identical to psoriasis. Keratodermia is found in less than a third of patients. Ulcers and erosions can occur in the mouth and are typically not painful. Circinate balanitis is a superficial erosion on the glans penis and is seen in 20-50% of patients. Finally, nail changes can occur with accumulation of hyperkeratotic material beneath the nail.

Miscellaneous
Cardiac involvement can occur in up to 10% of patients with either conduction problems or aortic insufficiency. Rarely, peripheral or cranial neuropathies can occur.

Radiographic features

The basic features have been alluded to with discussion of the other spondyloarthropathies. The spine involvement is similar to that seen in psoriatic spondylitis with more asymmetric involvement of the sacroiliac joints and non-marginal syndesmophytes. Reactive periostitis also occurs particularly around the calcaneous. Plantar spurs are very characteristic of Reiter's syndrome.
Treatment

Medications used to treat Reiter's syndrome include NSAIDs, intra-articular steroids, occasionally oral steroids, sulfasalazine, methotrexate, and azathioprine. Methotrexate is presently felt to be contraindicated in patients with Reiter's syndrome and HIV infection due to data that suggests that methotrexate may hasten the progression of the HIV disease. All patients with Reiter's syndrome should be considered for HIV testing.

Antibiotics may have a role in preventing the development of a chronic disease state but this is presently not fully elucidated. One should consider a prolonged course (2-4 weeks ?) of tetracycline or another antichlamydia agent in patients with postvenereal Reiter's syndrome.

Prognosis

Unfortunately, Reiter's syndrome tends to be a recurrent disease. A minority of patients may have a single episode and another small group may develop severe persistent disease. Most episodes last less than six months. Patients with HIV infection and Reiter's syndrome/psoriatic arthritis often have more severe persistent form of disease.


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other types of spondyloarthropathies

Post by Mike Bartolatz » Thu Dec 01, 2005 7:11 pm

Continuing Medical Education: Spondyloarthropathies. University of Washington, Seattle
Edited By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

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Other types of spondyloarthropathies
Juvenile ankylosing spondylitis

This entity is characterized by pauciarticular lower extremity arthritis usually in boys and often with a family history of spondyloarthropathy. Most are B27 positive. The peripheral arthritis usually begins first followed later by the axial skeletal involvement.
Late onset peripheral spondyloarthropathy

At the other end of life, a syndrome of pauciarticular joint involvement with marked lower extremity swelling which later evolves into more typical ankylosing spondylitis has been described. It has been reported to occur in the sixth and seventh decades of life and does not respond well to NSAIDs as do other spondyloarthropathies. Patients may have marked elevation of the ESR and constitutional symptoms as well.
Enteropathic spondylitis

Inflammatory Bowel Disease
Peripheral arthritis: Both Crohn's disease and ulcerative colitis can be associated with a peripheral arthritis in about 20% of patients. The large joints of the lower extremities are typically affected and the arthritis waxes and wanes with the activity of the bowel disease. The peripheral arthritis is not a HLA B27 associated process.
Spondylitis: About 20% of patients may have evidence of sacroilitis and some 20% of these patients may progress on to actual ankylosing spondylitis. Only 50% of patients with sacroilitis carry the HLA B27 haplotype. The course of the spondylitis does not correlate with the bowel activity.
Whipple's Disease
Arthritis is the presenting complaint in 60% and occurs at some time in 90% of patients with Whipple's disease. The arthritis is a migratory oligoarthritis. Patients also have an increased prevalence of sacroilitis and ankylosing spondylitis. Diagnosis is made by the history of persistent diarrhea and possibly protean other manifestations, along with PAS positive material in the lamina propria of the gut on biopsy. Treatment is with prolonged antibiotics.

Bowel Bypass Arthritis-Dermatitis Syndrome
Intestinal bypass for obesity has been associated with a interesting syndrome of arthritis and dermatitis occurring in 8-36% of patients. The arthritis in typically oligoarticular in nature and very painful. The etiology is felt to be due to immune complexes containing bacterial products from the gut. Dermatitis is also present in up to 80%. Treatment is with NSAIDs, antibiotics to reduce bacterial load, or reanastomosis of the bowel.

Undifferentiated spondyloarthropathy

This category is used to include those patients who do not fit any particular category of disease or may have a combination of features. Many of these patients may have a chronic inflammatory monoarthritis in the setting of B27 haplotype, heel pain caused by calcaneal periosititis, or recurrent dactylitis (sausage digits).

Uveitis is a feature of almost all of the spondyloarthropathies to one degree or another. Any young male who presents to an ophthalmologist with uveitis should be evaluated for a spondyloarthropathy.




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Resources

Post by Mike Bartolatz » Thu Dec 01, 2005 7:12 pm

By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

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Resources
Bibliography

Schumacher HR, Klippel JH, Robinson DR (eds): Primer on the Rheumatic Diseases, Tenth Edition. Arthritis Foundation, Atlanta, Georgia, 1993.
Excellent source for quick information on the rheumatic diseases. Generally more detailed than medicine textbooks.

Kahn MA (ed): Ankylosing spondylitis and related spondyloarthropathies. Spine. State of the Art Reviews 1990;4:497-688.
A more detailed source of information on this subject.

Kahn MA, van der Linden SM: A wider spectrum of spondyloarthropathies. Semin Arthritis Rheum 1990; 20:107-113.
Discusses the continuum of disease associated with the HLA-B27 antigen.

Kahn MA, van der Linden SM, Kushner I, et al: Spondylitic disease without radiologic evidence of sacroilitis in relatives of HLA-B27 positive ankylosing spondylitis patients. Arthritis Rheum 1985; 28:40-43.

Calabrese LH: Human immunodeficiency virus infection and arthritis. Rheum Dis Clin N Am 1993; 19:477-489.

Blocha KLN, Sibley JT: Undiagnosed chronic monoarthritis. Arthritis Rheum 1987; 30:1357-1361.
Discusses the etiology of chronic inflammatory monoarthritis on long term follow-up. Sixty-five percent were still undiagnosed at 2 years but approximately 15% ended up with the diagnosis of spondyloarthropathy and 8% with rheumatoid arthritis.

Review questions

A 27 year old male with severe ankylosing spondylitis was involved in a minor car accident. He complains about neck pain but routine films demonstrate only changes of the spondylitis including ankylosis of multiple cervical segments. A likely cause of this patients neck pain is: (one best answer)
Muscle strain from the accident.
Flare of the ankylosing spondylitis from the trauma.
Fracture through an ankylosed cervical disc space.
Insufficiency fracture through a cervical vertebrae.
Desire for large insurance settlement.
A 38 year old male comes to your office with a 3 week history of swelling and pain in the right ankle as well as several the toes of both feet. In addition, the left heel is very painful. Associated with these is a history of a urethral discharge and frequent loose stools. Diagnostic considerations include: (may be more than one right answer)
Whipple's disease
Reiter's syndrome
HIV infection
Inflammatory bowel disease
Early rheumatoid arthritis
A 24 year old female comes to the office with a 3 month history of low back pain particularly bad in the morning and better with activity. There is tenderness over both sacroiliac joints. X-rays of the pelvis show a question of right sided sacroilitis. The next choice for diagnostic testing to evaluate the possibility of ankylosing spondylitis might be: (one best answer)
HLA-B27 antigen
Sedimentation rate
CT scan of sacroiliac joints
X-rays of the lumbar spine
Repeat AP pelvis in 6 months
Radiographic features of ankylosing spondylitis include all of the following except: (one best answer)
Syndesmophytes
Facet joint fusion
Reactive periostitis
Disc space narrowing
Sacroilitis





Answers 1. c 2 b&c 3. c 4. c
Disclaimer

This resource has been provided by the University of Washington Department of Orthopaedics and Sports Medicine as general information only. This information may not apply to a specific patient. Additional information may be found at http://www.orthop.washington.edu or by contacting the UW Department of Orthopaedics and Sports Medicine.




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additional links

Post by Mike Bartolatz » Sat Dec 03, 2005 3:34 pm

--------------------------------------------------------------------------------

http://www.uveitis.org/medical/articles ... lab27.html
http://www.iritis.org/forum/viewtopic.php?t=849
http://www.emedicine.com/med/topic3098.htm
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MHC Class I disorders, Ankylosing spondylitis, etc

Post by Mike Bartolatz » Sat Aug 26, 2006 8:37 pm

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HLA-B27

Post by stressedwife » Sat Feb 17, 2007 9:11 am

I have been doing some research on HLA since we received the blood tests saying it is present in my husband.

1) Is there any website that explains the likelihood of passing this down to our children?

2) From what I have read it is much more likely to occur in males than females. Is this correct?

3) As well, how likely is it in siblings? HIs sister is sure she has AS but I told her to go get a blood test. Can she have AS without HLA-B27 being present?

We are waiting on ultrasounds for his liver - his nurse read me his numbers and levels that should be between 0 and 40 are reading in the 200's. I have been reading the AS sites for links between the liver/kidneys and AS but I guess we will have to wait to see the doctors next week to get some more answers.

Again thank you for this web site - it offers a great deal of information that helps me to ask the right questions when we see the doc's. My husband is finally recognizing that this is not going to go away and has started reading some of your posts so again thank you.

Theresa

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Post by Mike Bartolatz » Sat Feb 17, 2007 12:59 pm

I'm not a doctor nor an expert in genetics.
many individuals with the HLA B27 gene never get any of the spondyloarthropathies or uveitis. very few people with SA get uveitis as well. as to the other medical stuff only your doctors can sort that out as there are many causes for increased liver enzymes.
the information provided here is just that information for you and your DOCTORS to consider in treatmen of your conditions.

I wish I could be of more help.
Mike
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stressedwife
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Post by stressedwife » Sat Feb 17, 2007 3:46 pm

okay - thank you

Just wondered if you knew of any websites that might provide some further information. We will discuss this with our doctors - your site just seems so informative I thought I would throw it out there.

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