sign in sign up
<<
Home , Hypermobility (joints)

Instability due to disorders of metabolism and inflammation

Chris Holroyd Consultant Rheumatologist

University Hospital Southampton NHS Foundation Trust Outline

● Overview of hypermobility

● Genetic causes of hypermobility

● laxity in inflammatory joint disease Hypermobility

● Denotes an increased range of joint movement due to joint laxity

● In general, joint mobility is pronounced at birth and declines throughout childhood and thereafter ● More prevalent in females and Asians ● Strongly heritable – twin studies 70% variance accounted for by genetic factors

● Many individuals will be asymptomatic

● May lead to joint pain, dislocation and premature

● Important to exclude underlying genetic causes of collagen abnormalities Joint laxity

● Causes of joint laxity seen in ● Genetic disorders of collagen metabolism ● (Benign) Joint hypermobility syndrome ● Marfan’s syndrome ● Ehlers-Danlos syndrome

● Inflammatory disorders ● ● Systemic erythematosus (SLE) Joint hypermobility syndrome (JHS)

● Sometimes referred to as benign joint hypermobility syndrome

● Common disorder - under diagnosed

● Initially described as “the occurrence of symptoms in otherwise healthy hypermobile individuals”. Increasingly recognised as a complex genetic disorder

● defined by the association of generalised joint hypermobility, joint instability complications, widespread musculoskeletal pain, and (minor) skin symptoms

● Most regard it as the same as Ehlers-Danlos Syndrome – hypermobility type (EDS-HT; EDS type III) Epidemiology

● Epidemiology ● Poorly described and underestimated. Most evidence is observational ● Prevalence estimated at 0.2% (men)-0.6% (women) in Europe and US. Other authors state 2% ● Phenotype present in 40% of patients attending rheum clinic in UK1 ● More common in females ● ?hormonal role (undetermined) ● JHS females have reported symptoms worse immed. before (peak serum estrogen)

1. Grahame et al, Rheumatology 2004 Genetics

● Autosomal dominant trait with incomplete penetrance

● 50% chance of an affected patient transmitting the mutated gene, likelihood of developing JHS may depend on other intrinsic and environmental factors - sex, age, weight, diet, sport habits, trauma.

● Although perceived to be genetic origin, genetic mutations have not been repeatedly identified (unlike other forms of EDS) 1 ● Single family study suggested mutation in COL3A1 (codes for type 3 collagen) but not identified in subsequent studies

●1. Narcisi,Presently Human molecular “the gene” genetics, 1994for JHS is unknown Clinical manifestations

● Beighton Hypermobility scale (Beighton PH, 1973 Musculoskeletal manifestations

● Recurrent joint instability, , dislocation

● Chronic non-inflammatory joint or spinal pain without apparent structural abnormality ● Similar to that seen in patients with FMS and other chronic pain syndromes

● Secondary OA or spondyosis changes

● Intensity of pain appears to increase over time

● Avoidance of (painful) movement (kinesiophobia) leads to muscle deconditioning, adverse posture, and loss of function, and reduced quality of life Extra-articular

● Skin – reduced skin thickness (occ. visibly transparent), increased skin stretch, impaired scar formation, stretch marks

● Pelvic floor, diaphragm, abdo wall weakness

● Depression, anxiety

●

● Autonomic disturbance – syncope, palpitations, postural hypotension, bowel disturbance – in 60% 1998 Beighton diagnostic criteria

● THE 1998 BRIGHTON REVISED DIAGNOSTIC CRITERIA FOR THE BENIGN JOINT HYPERMOBILITY SYNDROME (BJHS)Major criteria ● 1 A Beighton score of 4/9 or greater (either currently or historically) 2 for longer than 3 months in 4 or more

● Minor criteria ● 1 A Beighton score of 1, 2 or 3/9 (0, 1, 2, or 3 if aged 50+) 2 Arthralgia in one to three joints or or or / 3 Dislocation in more than one joint, or in one joint on more than one occasion 4 Three or more lesions (e.g., epicondylitis, , ) 5 Marfanoid habitus (tall, slim, span > height; upper segment:lower segment ratio less than 0.89, arachnodactyly) 6 Skin striae, hyperextensibility, thin skin, or abnormal scarring 7 Eye signs: drooping eyelids or myopia or antimongoloid slant 8 Varicose veins or hernia or uterine/rectal prolapse.

● The BJHS is diagnosed in the presence of two major criteria or one major and two minor criteria or four minor criteria. Two minor criteria will suffice where there is an unequivocally affected first-degree relative. BJHS is excluded by the presence of Marfan or Ehlers-Danlos syndromes (other than the EDS Hypermobility type formerly EDS III) as defined by the Ghent 1996[10] and Villefranche 1998[11] criteria, respectively. Major and minor criteria 1 and 2 are mutually exclusive. ● From Grahame R, Bird HA, Child A, et al. The revised (Brighton 1998) criteria for the diagnosis of benign joint h ypermobility syndrome (BJHS). J Rheumatol 2000;27:1777-1779. ● JHS patients often also display increased skin stretchiness, marfanoid habitus, and other manifestations, overlapping with other heritable disorders of (HDCTs). Rheumatologists … Hypermobility

Autonomic dysfunction

Deconditioning

Anxiety and fatigue Chronic widespread pain Management

● Physio ● Muscle strengthening ● Restore ● Restore movement

● Occupational therapy ● Protect unstable finger joints ● Joint protection advice

● Podiatry – patients commonly have pes planus and over-pronation – insoles may help

● Psychology

● Medical – simple analgesics, NSAIDs. Steroid injection if isolated soft tissue lesion (?increased risk of rupture/ delayed and poor healing Ehlers-Danlos syndrome

● Described by Ehler and Danlos in 1900

● Heterogenous group of generalised connective tissue disorders associated primarily with abnormalities of collagen synthesis, structure or function (other enzyme, genetic changes have also been linked)

● Due to the multimetric structure of collagen, a defect in one allele can inactivate 93% of the total product for both alleles (contrast to enzymatic metabolic disorders)

● Primarily affects joints, skin and blood vessel walls

● 6 main types of disease – reclassified in 1997

● Incidence varies with type 1 in 100,000 (type IV) - 1 in 20,000 (type 1) Revised classification of Ehlers-Danlos syndrome, Villefranche 1997 Clinical features

● Vary according to type of disease ● Classic Ehlers-Danlos (Type I, II) ● Type II generally less severe ● Hypermobility, bruising, cigarette paper scars, hyperextensible skin, MVP, prem birth

Other types

● Type III – same as JHS

● Type IV (vascular) – severest – reduced life expectancy – 45 years due to complications such as arterial wall rupture, colonic, uterine rupture. Characteristic facial appearance. Joint hypermobility limited to small joints of hands

● Type VII – mainly joint symptoms, recurrent dislocations, CDH Management

● Multidisciplinary approach

● Refer to genetics to correctly establish type of Ehlers-Danlos syndrome

● Patient education – esp Type IV – prompt medial attention even with vague symptoms

● Generally supportive therapy

● Surgery – occasionally for joint instability, secondary OA Marfan’s syndrome

● First hereditable connective tissue disease to be described (by Marfan in 1896)

● Caused by a heterozygous mutation in gene FBN1 which encodes matrix -1

● Autosomal dominant ?increases with advanced paternal age

● Prevalence 1 in 5000-10,000

● No racial or gender variation

● MSK, eyes, cardiovascular systems Clinical features

● MSK th ● tall >95 centile for height ● Arm span greater than height ● arachnodactyly ● High arched palate ● Scoliosis ● Pectus excavatum, carinatum ● Joint laxity ● Pes planus

Other features

● Ocular ● Upward subluxation of the lens – 60% - usually bilateral

● Cardiovascular ● MV prolapse ● Dilation of the ascending aorta – cystic medial necrosis – 60%-80% - most common cause of mortality due to aortic dissection ● MR and AR Ghent classification criteria

or FNB-1 mutation

Needs major criteria in at least 2 different organs and involvement of a 3rd organ Management

● Refer to genetics to test for fibrillin mutation

● Annual echocardiogram. Prophylactic surgery once aortic root ~50mm ● ?ACE-I/ AG2 may reduce rate of aortic dilatation

● Annual opthalmic review

● Orthopaedic input – pectus abnormalities, scoliosis Joint laxity as a result of inflammatory disease

● Rheumatoid arthritis

● SLE Rheumatoid Arthritis

● Autoimmune Inflammatory arthritis

● Incidence in UK 0.5-1%

● 3 x more common in women

th th ● Peak incidence 4 – 6 decades

● Primarily involves of joints

● ?cause – likely genetic susceptibility (HLA DR4, DRB1)/ increased prevalence amongst twins and if positive family history

● + environmental factors – bacterial, viral – parvovirus, hepatitis, smoking ● Pannus formation

● Synovium becomes laden with macrophages,lymphocytes, fibroblasts, and multi-nucleated giant cells (resemble osteoclasts)

● Synovial membrane (pannus) expands, actively invades and erodes surrounding bone and cartilage

● Numerous cytokines released, Controlled by T cells

● TNF-alpha, Il-1 key. Others IL-6, 1L-12, 1L-15….

● B cells also important – autoantibody production

Treatment

● Changed dramatically over last 15 years ● Aim is to prevent joint laxity and structural damage ● Early referral and diagnosis ● Aggressive early management “window of opportunity” with use of combination DMARDs early on. Usually MTX and HCQ ● Monthly follow-up and dose escalation ● “Treat to target” – aiming for disease remission (DAS <2.6) ● Widespread use of MSK USS to detect subclincal ● Anti-TNF and other biologic agents when appropriate SLE

● 9x more common in women ● >95% ANA positive, dsDNA 40-85% MSK involvemnent

● Arthralgia ++ ● Non-erosive arthritis

● Jaccoud ● 10-35% ● Capsular and periarticular condition affecting hands primarily ● Ulnar drift (subluxation of MCPJs) oftne first sign, then z thumb, swan neck... ● Due to lax joint capsules, and as a result of capsular periarticular fibrosis or synovial vasculitis ● Initially reversible but can become fixed due to fibrosis Summary

● Causes of joint laxity seen in Rheumatology ● Genetic connective tissue disease ● JHS ● Ehlers-Danlos ● Marfans

● Joint laxity as a result of inflammatory disease ● RA ● SLE Any questions?