2. Some words Seronegative – no detectable antibodies (self-reactive in this case) Spondyloarthropathy – vertebral joint problems Spondylarthritis – vertebral joint problem caused by inflammation Ankylosing – fusing, fused

3. These are groups of conditions affecting the spine and peripheral joints which cluster in families and are linked to certain type 1 HLA antigens. The joint involvement is usually more limited than that seen in RA and its distribution is different. There are associated extra-articular and genetic features. These diseases occasionally present in childhood.

4. Histologically the synovitis itself is difficult to distinguish from that of RA, but there is no production of rheumatoid factors-hence seronegative. Anti-CCP is usually negative. Inflammation of the enthesis (the junction of ligament or tendon and bone) and joint ankylosis develops more commonly than in RA.

5. All are associated with in increased frequency of sacroiliitis and an increased frequency of HLA-B27.

6. A Ankylosing spondylitis (the prototype) P Psoriatic arthritis R Reactive arthritis Formerly called Reiter’s syndrome) E Enteropathic arthritis U Undifferentiated spondyloarthropathy PURE-A Mnemonic is PURE-A (sort of like purée)

7. Why are these diseases classified together? H HLA-B27 association E Enthesitis (both juxtaärticular and extraärticular) A Axial skeleton arthritis (generally secondary to juxtaärticular enthesitis) Spondylitis (inflammation of vertebral bodies) Sacroiliitis (inflammation of sacroiliac joint) P Peripheral arthritis (generally a synovitis) Asymmetric (cf rheumatoid arthritis) Extra articular Extra articular manifestations (besides enthesitis) S Seronegativity Rheumatoid factor and ANA negative

8. Etiology The common etiological thread of these disorders is their striking association with HLA-B27, particularly ankylosing spondylitis(AS). HLA type B27 is a finding in more than 90% of Caucasians with AS but only 8% of controls. The role of class 1 HLA antigens in the pathogenesis is supported by the fact that HLA-B27 transgenic mice spontaneously develop arthritis, skin, gut and genitourinary lesions.

9. There are clues that infections play a role, possibly by molecular mimicry, with parts of the organism which are structurally similar to the HLA molecule triggering cross-reactive antibody formation. This is unproven. AIDS is shown to increase the prevalence of reactive arthritis and spondylitis in sub- Saharan Africa even in the absence of HLA-B27. The explanation for this changing epidemiology is unclear.

10. The types of arthritis that fallow a precipitating infection are called reactive arthritis. The specialized immune systems of the gut and genito- urinary mucous membranes may also play a causal role, perhaps reacting to local infections or to antigens which across the damaged mucosa.

11. ANKYLOSING SPONDYLITIS(AS) This is a chronic inflammatory disorder of the spine affecting mainly young adults. It occurs worldwide and affects 1% of men and 0.5% of women in Caucasian populations. The frequency of AS in different populations is roughly paralleled by the incidence of HLA-B27. Africans and Japanese have a low incidence of both HLA-B27 and AS, while the North Americans have a high incidence of both.

12. . There are at least 24 subtype of HLA-B27. Some appear to increase the risk; other have a protective role. Twin studies indicate a much higher disease concordance in HLA-B27- positive monozygotic(up to 70%) twins than in dizygotic twin(about 20-25%).

15. CLINICAL FEATURES:-- Episodic inflammation of the sacroiliac joints in the late teenage years or early twenties is the first manifestation of AS. Pain in one or both buttocks and low back pain and stiffness are typically worse at morning and relieved by exercise. Initially the diagnosis is often missed because the patient is asymptomatic between episodes and radiological abnormalities are absent.

16. Retention of the lumber lordosis during spinal flexion is an early sign. Later, para spinal muscle wasting develops. The presence of three of the four fallowing indices in adult more than 50 years with chronic back pain indicate AS:-

18. 1- morning stiffness more than 30%. 2-improvement of back pain with exercise but not rest. 3-awakening because of back pain during second half of the night only. 4-alternating buttock pain. Salient features: 1- 'question mark' posture(due to retention of lumber lordosis, fixed kyphoscoliosis of the thoracic spine with compensatory extension of the cervical spine) 2- protuberant abdomen.

19. Extra-articular features 1- anterior uveitis(25%)& conjunctivitis(20%) 2- prostatitis (80%) of men ; usually asymptomatic 3- cardiovascular disorders ;aortic & mitral incompetence(4% of patients who have had the disease for over 15 years), conduction defects, pericarditis 4- amyloidosis 5- apical pulmonary fibrosis.

20. Remember: Five 'A's of AS: apical fibrosis, anterior uveitis, aortic regurgitation, achilles tendinitis& amyloidosis.

21. INVESTIGATION:--- -Blood :- the ESR and CRP are usually raised -HLA-testing is rarely of value because of high frequency of HLA-B27 in the population. -X-rays:-the medial and lateral cortical margins of both sacroiliac joints lose definition owing to erosions eventually become sclerotic.

22. The earliest radiological appearances in the spine are blurring of the upper or lower vertebral rims at the thoracolumbar junction(but seen on lateral X-ray) caused by an enthesitis at the insertion of the intervertebral ligaments. Sacroilitis, sclerosis, squaring of vertebrae, & bridging syndesmophytes ( marginal bony spurs that bridge the adjacent vertebral bodies) are typical radiographic findings. -MRI: demonstrates sacroiliitis before it seen on x-ray.

23. treatment

24. Keep it moving – exercise program to maintain posture and range of motion – physiotherapy and hydrotherapy NSAIDs – first line of pharmacotherapy Sulfasalazine (not other DMARDs) Anti-TNF-a – can really produce profound and sustained reduction in disease activity Infliximab (mouse Ab), IV 3-5mg/kg, bi-monthly Etanercept (TNFa receptor Ab), SC 50mg once weekly Adalimumab (human Ab), SC 40mg biweekly

25. Intra-articular steroid injections for peripheral synovitis Surgery – arthroplasty where sever hip arthritis causes pain Uveitis – local glucocorticoid use with mydriatic agents Cardiac disease treatment (pacemaker, aortic valve replacement)

26. PROGNOSIS:-- With exercise and pain relief, the prognosis is excellent and over 80% of patients are fully employed. Anti-TNF therapies are likely to reduce the morbidity of sever disease, reducing the risk of permanent spinal stiffness and progressive peripheral joint disease. Patients should be made aware that there is a risk of passing HLA-B27 gene to50% of their children. HLA-B27 positive offspring then have a 30% risk of developing AS.

28. Reactive arthritis is a sterile synovitis, which occurs fallowing an infection. Seronegative spondyloarthropathy develops in 1-2% of patients after an acute attack of dysentery, or sexually acquired infections like nonspecific urethritis in the male& nonspecific cervicitis in female. In male patients who are HLA-B27 positive, the relative risk is 30-5-%, being HLA-B27 positive is not obligatory. However, women are less commonly affected.

29. Reiter's syndrome is a special entity of reactive arthritis in which the fallowing triad of symptoms are found:- -arthritis of large joints - inflammation of the eyes in the form of conjunctivitis or uveitis and -urethritis in male and cervicitis in women.

30. CLINICAL FEATURES The onset is typically acute, with urethritis, conjunctivitis(50%)& oligoarthritis of large & small joints of lower limbs 1-3 weeks after sexual experience or bacillary dysentery. There may be systemic disturbances like weight loss, fever, & vasomotor changes in feet. The onset could be sub- acute or insidious.

31. There may be only asymmetric oligoarthritis with no clear preexisting urethritis or dysentery but radiological features & Achilles tendonitis are further clues.

32. EXRTA ARTICULAR FEATURES : 1- circinate balanitis; 20-50%, starts as vesicles rupture to form superficial erosions on the prepuce & glans penis. These lesions are painless.

34. 2- keratoderma blenorrhagica 15%; waxy yellow –brown vesicopapules that may coalesce to form large crusty plaques. Palms, soles & scrotum are typical sites. Chronic or recurrent disease develops in 60% of patients & not necessarily related to further infection.

35. Low back pain & stiffness due to sacroiliitis can occur together with cardiac& CNS abnormalities similar to AS. Other joints like ankles, midtarsal & MCP joints are involved in chronic reactive arthritis.

36. INVESTIGATIONS: : acute phase responses are positive, Anemia of normochromic normocytic type are clearly evident findings. Synovial fluid reveals inflammatory findings- low viscosity& turbid, with giant macrophages(Reiter's cells).

37. GUE for mucoid threads(urethritis), vaginal swab for Chlamydia & GSE for dysentery together with radiological changes are other clues for diagnosis.

38. MANAGEMENT In the first attacks, symptomatic treatment with analgesics & NSAIDs is helpful together with intra articular steroid injections. Systemic steroids are rarely needed. In sever disease& intractable keratoderma blenorrhagica anti- rheumatic drugs like methotrexate & azathioprine are warranted.

39. Chlamydial infections should be treated with short course tetracycline. Anterior uveitis requires systemic steroids. TNF is an inflammatory cytokine& TNF blocking agents like etanercept& infliximab have a rule in treatment of reactive arthritis.