Typical features on radiographs in patients with PsA \200 General: enthesophytes; periosteal new bone (often juxta-articular); often no periarticular osteopaenia. Pelvis: irregular/unilateral sacroiliac changes; hip arthritis; enthesophytes ; osteitis pubis. Spine: syndesmophytes; facet joint arthritis; poste- rior element new bon e formation (enthesophytes and periosteal apposition); spondylodiscitis. Peripheries: DIPJs : juxta-articular bone; widening joint space; \200\230 \202 ange \200\231 osteophytes. Ph alanges: dactylitis; diaphyseal thickening; tuft changes; soft tissue swelling (dactylitis) \200 Axial skeleton \200 Signs in the neck and spine are non-speci \201 c, although marked global restriction of mo vement can occur. PSORIATIC ARTHRITIS 222 Figure 7.6 DIPJ arthritis in PsA. Flanging of periarticular bone, increased joint width (ri ght), abnormal distal phalanx bone texture changes (in the digit on right with dactylitis) and a paucity of OA features (e.g. subchondral sclerosis, cysts and osteophytes). Figure 7.8 Juxta-articular new bone (periosteal whiskering) of the great toe distal phalanx in PsA. Note the relatively normal joint appearance. Figure 7.9 Juxta-articular bone at calcaneocuboid joint. A plantar spur can be associated w ith PsA. MR-identi \201 ed changes in the nail-bed associated with DIPJ arthritis may be speci \201 c for PsA and may be detect- able using extremity (0.2T) MR. Differential diagnosis \200 Figure 7.7 PsA neck. Marginal and paramarginal syndesmophytes, \202 orid posterior elemen t periosteal apposition and facet joint involvement. Where there is obvious chronic synovitis in a number of small joints the main differential diagnosis is RA. Generalized OA will be the main differential diagnosis of multiple DIPJ in volvement. Look for nail pits (associated with PsA not OA). Be suspicious of a diagnosis of OA in a patient with Ps (or previous history of it or Ps in \201 rst degree relative) in an \200\230unusual \200\231 joint for OA (e.g. ankle or subtalar), where there has been n o previous signi \201 cant trauma. Like PsA, all SpAs are characterized by dactylitis, joi nt and enthesis lesions. The enthesopathic/periosteal lesions of PsA can be mistaken for \201 bromyalgia. MR Distinctive patterns of MR abnormality for dactylitis and PsA-related DIPJ arthritis are now recognized, although results need substantiating: \200 MR has not yet been shown to discriminate sarcoid from PsA/SpA-related dactylitis. MR may n ot be as useful in identifying in \202 ammatory spinal lesions in PsA as it is in AS. CHAPTER 7 The spondylarthropathies 223 Patients treated with MTX are 9 times more likely to bene \201 t and 5 times less likely t o stop treatment com- pared with patients treated with gold compounds \200\223 the latter having shown some ef \201 cacy in PsA, given either as aurano \201 n 3 g/day or monthly i njections. RCT data have shown sulphasalazine, le \202 unomide, and anti-TNFA therapies ca n improve PsA symptoms in the short term. Le \202 unomide and notably anti-TNFA therapies have a signi \201 cantly improve Ps as well. Ciclosporin A, antimalarials D-penicillamine and azathio- prine show some ef \201 cacy in small, open label studies. Antimalarials can aggravate Ps, however. Overall, conventional DMARDs have not shown ef \201 cacy in treatin g axial PsA disease. Prognosis \200 Worse prognosis is associated with polyarticular presen- tation, high ESR/CRP and IgA and H IV status. Persistent dactylitis is associated with erosive disease of underlying small joi nts. HLA B27, B39 and DQw3 are associated with disease progression but DR7 is protective. S tudies linking synovial \202 uid constituents to prognosis fail to represent the complete range of PsA subtypes. Figure 7.10 PsA toe. Juxta-articular new bone (periosteal apposition) of distal \201 rst metatarsal head. Current controversies Diagnostic issues \200 Chronic sarcoid, like PsA, can involve entheses and periostea particularly around the hindf oot and lower leg (e.g. plantar fasciitis). PsA spondylitis can be mistaken for chronic mec hanical back (or neck) pain. Most controversies probably arise as a consequence of varied case ascertainment in clinical studies. Is PsA one condition with many and varied musculoskel- etal lesions or are there distinct conditions? Can PsA be adequately defined without extensive Primary Care based cap ture of a broad range of possibly affected patients with and without Ps? Will CASPAR perfor m appropriately in this respect? What is the main lesion in PsA? Enthesitis? Periostitis? S ynovitis? A review of the foremost textbook of muscu- loskeletal radiology would suggest no n-articular bone- related lesions are the most frequent across the PsA disease spectrum (se e Resnick 2002). What is the prevalence of PsA-sine-Ps? Is dactylitis always clinically evi dent? What is the spectrum of PsA-related spinal disease? For example how commonly is spond ylodiscitis or facet joint arthritis a feature of Psoriatic spondylitis? Do current diagnos tic methods under-estimate Ps-related musculoskeletal disease? In the spine? Current method s of identifying Psoriatic Enthesopathy are suboptimal and there may be diagnostic confusio n in patients otherwise thought to have \201 bromyalgia. Does MR discriminate PsA from al l phases of OA in DIPJs particularly in early disease? Treatment Objectives of disease management \200 To control symptoms and prevent disability through judicious use of NSAIDs and immunosuppre ssants. One-fourth of patients with PsA are dissatis \201 ed with the treatment they recei ve (see NPF 2002). Although PsA is often judged to be indolent, evidence suggests that, lif elong, PsA is associated with signi \201 cant indices of disability. \200 \200 Physical therapies There is little evidence to suggest what role physical therapy plays in PsA. Hand therapy review for assessing functional impact, and utilizing splinting and joint protection methods. Control of pain NSAIDs probably have a variable effect. Trying full dose over 4 weeks and s wapping to an alternative if no satisfactory effect occurs is appropriate. Immunosupression There is a de \201 cit of therapeutic trials in PsA. This and other subop timal aspects of the care of PsA patients have been addressed in principle through the aims of GRAPPA, an international group of clinicians convened to work toward facilitating resea rch into PsA. \200 Management issues \200 The role of physiotherapy and whether exercise helps or worsens PsA-related spondylitis in the short-term (symptom modi \201 cation) and long-term (?accelerated spinal damage). What measures should be adopted to gauge results in therpaeutic studies? Should different datas ets be used for different disease subtypes? Are anti-TNFA therapies cost-effective in PsA i n the long-term? Do they prevent radiological progression? Historically the use of therapies in PsA has followed from their established use in patient s with RA. Though anecdotal evidence for its ef \201 cacy can be found, methotrexate (MTX) has not been extensively studied. Studies suffer from low patient numbers, too short follo w-up, and other methodological \202 aws. PSORIATIC ARTHRITIS 224 Table 7.5 A summary of the major randomized controlled therapeutic trials in PsA Drug (reference) Patient characteristics RDBPCT* details Statistically signi \201 cant results Sulphasalazine (SZP) Clegg et al. (1996) 221 patients 36-week study. SZP 2 g/day. SZP signi \201 cantly effective according to composite pre-de \201 ned response measure. High response rate in placebo arm (44%) 24-week study. LEF 100 mg/day for 3 days then 20 mg/day 59% LEF vs. 30% placebo responded judged by PsARC Le \202 unomide (LEF) Kaltwasser et al 2004 190 patients with PsA + psoriasis - all patients having failed DMARD 12-week study. ETN 25 mg \227 2/week; sc injection ACR20 achieved in 59 vs. 12% placebo. PsARC achieved in 72% vs. 31% placebo. Response main tained for 2 years in later analysis Inhibition of radiographic progression at 2 years from later analysis [Mease et al. (2006a)] Etanercept (ETN) Mease et al. (2004) 205 patients, 40% on MTX 14-week study. INF 5 mg/kg iv regime ACR20 achieved in 58 vs. 11% placebo PsARC achieved in 77 vs. 27% placebo. Response maintai ned + inhibition of X-ray progression for 1 year in later analyzes In \202 iximab (INF) Antoni et al. (2005) 200 patients unresponsive to prior treatment Adalimumab (ALM) Mease et al. (2005b) 313 patients, 50% on MTX 24-week study. ALM 40 mg every 2 weeks ACR20 achieved in 58 vs. 14% placebo ACR20 achieved in 54 vs. 23% placebo. 185 patients all on MTX 24-week study, ALF 15 mg im weekly randomized 2:1 vs. placebo injection for 12 weeks. Outco me at 24 weeks (MTX contd only) Alefacept (ALF) human LFA-3/IgG1 fusion protein, which binds CD2 receptors on T cells to bl ock LFA binding on APCs Mease et al. (2006b) Table 7.6 New or potential future therapies for PsA Biologic agent Notes Onercept: a recombinant p55 TNF-binding protein, given as a weekly sc injection Is approved to treat psoriasis. Showed ef \201 cacy (ACR20) in a phase 2 study Is FDA approved as a once weekly sc injection to treat Ps. A small 12 week RCT in PsA showe d a trend for improvement vs. placebo. Efalizumab A recombinant humanized IgG1 mc antibody, which binds LFA-1/CD11a preventing T -cell-ICAM-1 binding (APCs and endothelium) Concerns about its safety led to a review of reported side effects (Scheinfeld 2006). Abatacept: Soluble receptor (CTLA-4+IgG-Fc fragment), which blocks T-cell-APC binding Has been studied in RA and psoriasis. Studies in PsA likely to follow Anti-Interleukin 12 (p40) antibody Downregulates Th-1 cytokines in psoriatic skin lesions. Untried as yet in PsA Anti-Interleukin 15. In \202 ammatory cytokine active in many in \202 ammatory conditions including Ps As yet no therapeutic studies in humans. Potentially important molecule to target Resources Assessment tools PsARC (Clegg et al., 1996). Response criteria adapted from a the rapeutic study of sulphasalazine in PsA. Review of assessment tools used in clinical trials (Mease et al., 2005c). Classi \201 cation criteria (CASPAR). See Taylor et al. (2006). Patient organizations/information UK: Psoriatic Arthritis Alliance. Available at: www. paal liance.org USA: National Psoriasis Foundation. Available at: www. psoriasis.org The Interna tional Federation of Psoriasis Associations. Available at: www.ifpa-pso.org/en/home ICD10 codes M07* M07.0* M.07.1* Arthritis mutilans M07.2* Psoriatic spondylitis M07.3* Othe r psoriatic arthropathies M09.0* Guidelines for physicians Kyle S, et al. (UK) British Society for Rheumatology (BSR) Guidel ine for anti-TNFA therapy in PsA. Rheumatology 2005; 44: 390 \200\2237 (www.rheumatology.or g.uk). Supplement 2 from Volume 64 (March 2005) of the Annals of Rheumatic Diseases contain s useful reviews about the clinical and radiographic assessment of PsA. Psoriatic and enteropathic arthropathies Distal interphalangeal psoriatic arthropathy Juvenile arthritis in psoriasis CHAPTER 7 The spondylarthropathies 225 References Antoni CE, Kreuger GG, de Vlam K, et al. In \202 iximab improves signs and symp toms of PsA: results of the IMPACT2 trial. Ann Rheum Dis 2005; 64: 1150 \200\2237. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of PsA: safety, ef \201 cacy an d effect on disease progression. Arthritis Rheum 2004; 50: 2264 \200\22372. Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radio- graphic progression in patients with PsA following 2y of treatment on etanercept. J Rheumatol 2006a; 33: 712 \200 \22321. Clegg DO, Reda DJ, Mejias E, et al. Comparison of sulfasalazine and placebo in the treatmen t of PsA. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996; 39: 201 3 \200\22320. Gladman DD. Psoriatic arthritis. In: Silman AJ, Symmons DPN (eds) Bailli re \200\231s Clinical Rheumatology, International Practice and Research, vol 9. London: Bailli re Tindall, 1995, 319 \200\22329. Mease PJ, et al. Alefacept in combination with MTX for the treatment of PsA: results of a r andomized placebo-controlled study. Arthritis Rheum 2006b; 54: 1638 \200\22345. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973; 3: 55 \200\22378. Goupille P, Vedere V, Roulot B, Brunais J, Valat JP. Incidence of oste- operiostitis of the great toe in PsA. J Rheumatol 1996; 23: 1553 \200\2236. Husted JA, Gladman DD, Farewell VT , Cook RJ. Health related quality of life of patients with psoriatic arthritis: a compariso n with patients with RA. Arthritis Rheum 2001; 45: 151 \200\2238. Nash P, Clegg DO. Psoriatic arthritis therapy: NSAIDs and traditional DMARDs. Ann Rheum Dis 2005; 64 (Suppl 2): 74 \200\2237. National Psoriasis Foundation. Benchmark Survey on Psori asis and PsA 2002. Available at: www.psoriasis.org/news Pitzalis C, Cauli A, Pipitone N, et al. Cutaneous lymphocyte antigen positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 1996; 39: 137 \200\22345. Resnick D. Psoriatic arthritis. In: Resnick D (ed.) Diagnos is of Bone and Joint Disorders, 4th edn. Philedelphia: WB Saunders Co., 2002, 1082 \200\223 109. Jones G, Crotty M, Brooks P. Interventions for PsA. Cochrane Database Syst Rev, CD000212, 2000. Kaltwasser JP, Nash P, Gladman D, et al. Ef \201 cacy and safety of le \202 u- nomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double blind randomize d placebo-controlled clinical trial. Arthritis Rheum 2004; 50: 1939 \200\22350. Sheinfeld N. Efalizumab: a review of events reported during clinical Kavanaugh A, Antoni CE, Gladman D, et al. The Infliximab Multinational PsA Controlled Trial (IMPACT): results of radio- graphic analyzes after 1 y. Ann Rheum Dis 2006; 65: 1038 \200 \22343. trials and side effects. Expert Opin Drug Saf 2006; 5: 197 \200\223209. Taylor W, Gladman D, Heliwell P, et al. Classi \201 cation criteria for psoriatic arthriti s: development of new criteria from a large inter- national study. Arthritis Rheum 2006; 54 : 2665 \200\22373. Mease PJ, Antoni CE, Gladman DD, Taylor WJ. PsA assessment tools in clinical trials. Ann Rheum Dis 2005c; 64: 49 \200\22354. Thune PO. The prevalence of \201 bromyalgia among patients with Mease PJ, Gladman DD, Kreuger GG. Prolog: Group for Research and Assessment of Psoriasis an d Psoriatic Arthritis (GRAPPA). Ann Rheum Dis 2005a; 64: ii1 \200\223ii2. psoriasis. Acta Derm Venerol 2005; 85: 33 \200\2237. Mease PJ, Gladman D, Ritchlin CT, et al. Adalimumab for the treat- ment of patients with mo derately to severrely active PsA: results of a double-blind randomized placebo-controlled t rial. Arthritis Rheum 2005b; 52: 3279 \200\22389. REACTIVE ARTHRITIS 226 Reactive arthritis De \201 nition No generally accepted diagnostic criteria exist for reactive arthritis (ReA ). ReA has historically been used as a broad term applied to a group of non-infectious auto immune ar- thritides occurring in association with preceding infection. Historically, one f orm of ReA has been known as Reiter \200\231s Syndrome (post-chlamydial arthritis). Reiter was a Nazi, involved in eugenics and many understandably believe he should not be credited with the honor of having a condi- tion named after him. Indeed, post-infectious reactive ar thritis had been described periodically since the 1500s and Reiter \200\231s 1941 paper des cribed a spirochaete-triggered condition and, overall, his paper contributed little to furt hering knowledge about reactive arthritis. \200 Etiology/pathphysiology General issues \200 Organisms triggering ReA may all persist after infecting humans and altering host immune re sponses. Each is Gram \200\223ve, invades mucosae, has lipopolysaccharide as part of their outer membrane, exerts intracellular para- sitism, and contains virulence factors, which h elps them evade host immune responses and survive. Bacterial pathogenicity may be enhanced by the pres- ence of HLA B27. See p. 214 for discussion of the role of HLA B27 in SpAs, mos t relevant for AS and ReA. A detailed review of ReA Pathophysiology can be found in Colmegn a et al. (2004). Lyme and viral arthritis are reactive arthritides, but are not generally SpA-like or HLA B2 7-related (see below) and are not considered here. Post-streptococcal arthritis (PSRA) is a n heterogenous reactive autoimmune entity. In some patients there are SpA-like features; ho wever, PSRA is not generally consid- ered part of the SpA group of conditions and is not co nsidered further here. Up to 1999 there were 32 different terms referring to (SpA-like, HLA B27-associated) ReA in the literature. The SpA-like ReA, dealed with here, is either trigg ered by urogenital or enteric infections. Enteric ReA \200 Many different organisms have been found or postulated to trigger ReA. Attempts to culture organisms from the joints of ReA patients have failed. Components of Yersinia, Salmonella, and Shigella (often lipopolysaccharide) have been detected in ReA joints. Yersinia and Salm onella can persist in gut mucosa and monocytes, which may act as a reservoir and transporte r of bacterial components. Urogenital ReA \200 Using a variety of techniques Chlamydia has been detected in the joints of ReA patients. Ch lamydial DNA in ReA joints does not correlate with the immune response and may vary inverse ly with Chlamydia-speci \201 c lymphocyte proliferation suggesting impaired T-cell respons es may be relevant. C trachomatis resides in synovial tissue (also primarily enthesial tiss ue) displaying an aberrant morphology and probably upregulating its hsp60 gene. Chlamydia i nfected monocytes release TNFA and may cause host T-cell apoptosis and can stimulate host c ells to release pro-in \202 ammatory soluble mediators (reviewed in Colmegna et al., 2004) . Epidemiology Incidence varies in the context of background population frequency of HLA B27 and prevalence of relevant infection. Most estimates are derived from Scandinavia. \200 In developed countries (and excluding South Africa), the estimated prevalence of ReA is 0.0 3 \200\2230.1% with an incidence of 5 \200\22313/100 000 for post-urethritis ReA and 5 \200 \22314/100 000 for post-enteric ReA. Prior to the evolution of HIV as a relevant in \202 u ence, urogenital ReA occurred in about 1% of men attending a sexual health clinic with non- gonoccocal urethritis. Accumulating reliable epidemiological data is compro- mized by varia ble case ascertainment: There are no clear criteria to consistently apply; C trachomatis is dif \201 cult to diagnose in women owing to dif \201 culty in identifying (the often sub -clinical) genital infection. Clinical features Key clinical features \200 ReA generally can affect people at any age, but mean age of onset is between 25 and 35 year s. Table 7.7 The characteristics of Reactive Arthritis (I) Causative organism* Incidence of ReA in those infected HLA B27 frequency %patients developing ReA within 30 days of infection Campylobacter jejuni 1 \200\2235%** 72% 85% Salmonella Typhimurium enteritidis, Paratyphi B and C and other Salmonella 1 \200\22314% 84% 94% Shigella S. \202 exneri/sonnei/dystenteriae 1% 80% 92% Chlamydia trachomatis 1% 80% 88% Yersinia enterocolitica O3, O8, O9 or Yersinia pseudotuberculosis 5 \200\22333% 75% 81% Though described as case reports or small series, ReA following Chlamydia pneumoniae, Chlam ydia Psittaci, Ureaplasma urealyticum are not included here as extensive data are not avail able. CHAPTER 7 The spondylarthropathies 227 ReA affects a number of musculoskeletal structures, but can also be systemic disease and ca use cardiac lesions. Yersinia ReA may mimic sarcoidosis (both cause periosti- tis and EN). Aortic ring dilatation and incompetence is a rare, late, but important feature. Co-morbidities All SpA features can occur: psoriaform rashes, diarrhea, uveitis. Chlamydia particularly has a number of non- rheumatological co-morbidities including pelvic symptoms, dyspareunia, urethral irritation, and infertility. \200 Keratoderma begins on palms or soles as pustules. They become horny crusts and can become c onfluent. Clinically and microscopically they are difficult to discriminate from pustular p soriasis. Circinate balanitis is painless. Erythema of the glans penis occasionally ulcerat es. Erythema nodosum is associated with Yersinia. Key features in history \200 In \202 ammatory-type back or lower limb symptoms within 6 weeks of relevant infection. Pa tients may report toe swelling or refer to \200\230sausage toe \200\231 (?dactylitis). A h istory of enteric symptoms is easy to elicit \200\223 diarrhea usually profuse \200\223 e xcept in Yersinia ReA where symptoms may be mild. Obtaining a full genitourinary history ma y require sensitive enquiry and an explanation of the relevance of questioning beforehand. Key features on examination \200 Investigations Laboratory \200 \200 iESR, CRP, and IgA. But RF and ANA are negative. Urogenital smear \200\223 often negative despite suspicion of Chlamydia infection. Urinalysis can be positive for leucocytes (steril e pyuria). Antibodies to relevant organism (>2 SD above upper limit of reference interval I gG + either iIgA or iIgM) might be suggestive of diagnosis in the presence of in \202 amma tory acute/subacute back pain, oligoarthritis or enthesitis, and evidence or suspicion of r ecent preceding urogenital or enteric infection. Common features: monoarticular joint selling; plantar fasciitis, positive sacroiliac stress tests, enthesitis mainly in lower limbs. Keratoderma and pustulosis on palms and soles of feet. Balanitis in urogenital ReA. EN in Yersinia infection \200\223 tender subcutaneous s welling or patches of soft-tissue tenderness often in lower limbs often with overlying skin erythema. \200 \200 Table 7.8 The characteristics of reactive arthritis (II) Clinical features Outcomes Peripheral arthritis Large joint \200\223 lower limb synovitis typically non-erosive; dactylitis 16%; Average duration 4 \200\2235 months Up to 70% of C trachomatis ReA patients develop recurre nt arthritic bouts Chronic recurrent arthritis 15 \200\22330% on average Overall small mino rity get erosive disease requiring long-term immunosuppressants. Increased severity and dur ation in those HLA B27+ Limb enthesopathy Heel pain, Achilles \200\231 or patella ligament insertional pain (30%) Unknown. Enthesopathy likely to be part of chronic musculoskeletal condition. Increased sev erity and duration in those HLA B27+ Axial in \202 ammatory symptoms Sacroiliitis 14 \200\22349%; spondylitis 12 \200\22326%; pelvic enthesopathy Increased severity and duration in those HLA B27+ Conjunctivitis occurs in the majority of Salmonella, Shigella and Campylobacter patients, i s often mild and missed. Eye disease Conjunctivitis (35%); iritis (5%); keratitis; corneal ulceration; episcleritis; retrobulbar neuritis; hyphema. Gastrointestinal Diarrhea; lesions resemble Crohn \200\231s/ UC on ileocolonoscopy or biopsy. Lesions can occur even in post-urethritis ReA (25%). The longer the duration of diarrhea th e greater the chance of ReA. Gut in \202 ammation can be subclinical with Yersinia. Chroni c ReA following Salmonella or Shigella infection occurs in 20% and <5% following Yersinia Almost exclusively occurs following Chlamydia trachomatis infection though sterile urethrit is can occur in some cases of post-enteric ReA. Chronic ReA following Chlamydia ReA in 17%. In post-urethritis ReA about 50% can get abnormalities on urine dipstick testing. Genitourinary Urethral pain and discharge; prostatitis; haemorrhagic cystitis; non-speci \201 c cervicit is bleeding/abdo pain; proteinuria, microhaematuria or aseptic pyuria Mucocutaneous lesions are common in all ReA types. Mucocutaneous lesions Keratoderma; palmar pustolosis; circinate balanitis (post-C trachomatis); oral ulcers; eryt hema nodosum (Yersinia ReA); hyperkeratotic nails Cardiac Aortic valve disease; conduction defects Symptomatic aortic valve disease rare and a late complication. ECG abnormalities in 14% pat ients. REACTIVE ARTHRITIS 228 Clinical utility of serum serological tests is modest; chie \202 y a consequence of subopt imal speci \201 city. In enteric ReA, stool culture often unhelpful by the time patients p resent with musculoskeletal features. HLA B27 often positive in severe or chronic ReA cases . Consider joint aspiration to rule out infection or crystal- induced monoarthritis. Consid er screening for HIV, syphilis and gonococcus in patients with evidence of C trachomatis in fection. Immunosupression \200 Oral GCs, e.g. 0.25 \200\2230.5 mg/kg/day initially; can be used empirically in severe case s. GCs are arguably more effective for the peripheral compared with the axial musculoskelet al lesions. In chronic cases, sulphasalazine (SZP; 2 g/day in bd or tds doses) has been sho wn in a RCT to be effective at controlling ReA (Clegg et al., 1996). Although methotrexate (MTX) is used frequently and is associated with some ef \201 cacy in ReA, no RCTs exist. C hronic ReA has been treated successfully with anti-TNFA. No formal therapeutic trial has be en done. \200 Imaging Radiographs Sacroiliitis: frequently unilateral. Enthesophytes (e.g. plantar fascia or Achilles \200\231 tendon insertion) can appear eroded (compared with smooth bone textur e as in DISH enthesophytes). Prognosis and natural history (Table 7.9) \200 ReA is usually mild and self-limiting (average duration 3 \200\2235 months), although can f ollow relapsing-remitting or aggressive chronic courses (up to 15%). About 75% of cases are in complete remission by 2 years. In enteric infection triggered ReA, diarrhea is usually short-lived though can last a month \200\223 self-limiting in the majority of cases. Altho ugh some enteric infections can persist, chronic troublesome symptoms are unusual. In the m ajority of people, the arthritis is non-erosive. The duration of arthritis varies. The pres ence of HLA B27 is linked to more severe dis- ease, higher likelihood of sacroiliitis, and extra-articular manifestations and persistent arthropathy. The greater the number of factor s below, the worse the prognosis: male gender; onset <16 years; family history of SpA; hip arthritis; an ESR>30 mm/h; poor NSAID ef \201 cacy; stiff lumbar spine; dactylitis MR High signal lesions on T2-weighted sequences at SIJs and sites of entheses (peripherally ) or showing joint synovitis, but also in spine disease, the corners of vertebrae (Romanus lesions) as per AS. 99mTc-MDP scintigraphy Characteristic tracer distribution particularly in lower limbs seen in severe cases. Mild cases often not highlighted by scintigraphy. \200 Differential diagnosis \200 Acute SAPHO, PsA, Sarcoid, ESpA, atypical AS can mimic ReA, particularly where enthesitis i s prominent. Crystal arthritis, gonococcus arthritis, Lyme disease, and coeliac disease are associated with monoarthritis. Treatment Patient information/advice \200 Table 7.9 Long-term (10-20y) prognosis of ReA: arthritis (from Colmegna et al 2004, with pe rmission) If no previous screening then counseling regarding genital testing of sexual partners and H IV testing important where Chlamydia infection suspected. Patient information booklets (e.g . arc in the UK). Counseling about potential chronicity. %of patients with end-point after infection with: \200 Yersinia Salmonella Shigella C trachomatis Recovered 45 40 20 30 Early disease management C trachomatis infection should be treated irrespective of symptoms or arthritis. Sexual partners should be traced and treated as well. \200 Arthralgia 20 20 NA* 68 Recurrent arthritis 6 22 18 38 Chronic arthritis 4 19 19 17 Antibiotics may be useful in urogenital ReA, but weaker evidence exists for enteric ReA. An early 3-month treatment course of lymecycline for urogenital ReA can substantially reduce the risk of chronic/recurrent ReA in patients and development of ReA in partners, but in th e long-term may not change the natural history of disease. Doxycycline for 10 days may be a s effective as giving it for 4 months to reduce the effects of ReA. Long-term cipro \202 o xacin provided no bene \201 t to ReA patients in a RCT (Sieper et al., 1999). Antibiotics probably make little difference to the outcome of Yersinia ReA. Pain control \200\223 NSAI Ds in full regular dosage and aspirate swollen joints where possible and consider intra-art icular glucocorticoid (GC) injection. May need to culture joint \202 uid if infection sus pected initially but steroid joint injection useful. Input from relevant (eye, sexual healt h, skin, or gastroin- testinal) specialist especially medical ophthalmologist for slit-lamp exam to exclude uveitis. AS 15 12 14 26 Radiological synovitis 20 14 32 49 Data not available Current controversies Diagnostic issues \200 \200 How many other infections can trigger ReA? Is infection with any Chlamydia organism or Urea plasma urealyticum a risk for (SpA-like HLA B27-related) ReA? Is mild ReA \200\223 manifes t for example just by self-limiting inflammatory low back symptoms or enthesitis \200\223 under-recognized ? Management and treatment issues The use of antibiotics remains controversial. \200 There may be short-term gains from treatment at CHAPTER 7 The spondylarthropathies 229 References Altman LK. Experts re-examine Dr Reiter, his syndrome, his Nazi the time of urogenital ReA presentation, but type and duration of antibiotics is debated. D o antibiotics alter the long-term outlook of ReA? Whether different antibiotics/regimes giv en for initial enteric or urogenital infection vary in their ability to reduce ReA incidenc e, severity or chronicity. Is MTX more ef \201 cacious than SZP in chronic ReA? Will le \202 unomide be ef \201 cacious in ReA? The role of anti-TNFA needs to be de \201 ned in severe chronic ReA. \200 past. Science. New York Times, March 7th 2000. Colmegna I, Cuchacovich R, Espinoza LR. HLA B27- associated reactive arthritis: pathogeneti c and clinical considerations. Clin Microbiol Rev 2004; 17: 348 \200\22369. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular mani- festations of the seronegative spondylarthropathies . Arthritis Rheum 1999; 42: 2325 \200\2239. \200 \200 Kaipanen-Seppanen O, Ano K. Incidence of chronic in \202 ammatory disease in Finland in 1995. J Rheumatol 2000; 27: 94 \200\223100. Resources Guidelines The Arthritis Research Campaign (arc). Available at: www.arc.org; Info rmation booklets and other disease-related information for physicians. Keat A. Reiter \200\231s syndrome and reactive arthritis in perspective. N Engl J Med 1983; 309: 1606 \200\22315. Pacheco-Tena C, Burgos-Vargas R, V zquez-Mellado J, Cazar n J, P rez-D az JA. A proposa l for the classi \201 cation of patients for clinical and experimental studies on reactive arthritis. J Rheumatol 1999; 26: 1338 \200\22346. Patient resources/organizations Managing Reactive Arthritis. Article by A Toivanen. Avail- able at: www.rheumatology.oxfordjournals.org/cgi/ content/full/39/2/117. Pope JE, Krizova A, Garq AX, Thiessen-Philbrook H, Ouimet JM. Campylobacter reactive arthri tis: a systematic review. Semin Arthritis Rheum 2007; Mar 12. Epub. Press N, Fyfe M, Bowie W, Kelly M. Clinical and microbiological follow-up of an outbreak of Yersinia pseudotuberculosis serotype Ib. Scand J Infect Dis 2001; 33: 523 \200\2236. Internet sites Webpage on Spondylarthritis American College of Rheu- matology. Available at : www.rheumatology.org/public/ factsheets/ Sieper J, Fendler C, Laitko S, et al. No bene \201 t of long-term cipro- \202 oxacin tre atment in patients with ReA and undifferentiated oligoarthritis: a 3-month multicenter doub le-blind, randomized placebo-controlled study. Arthritis Rheum 1999; 42: 1386 \200\22396. ICD10 codes M02.1 M02.3 Post-dysenteric arthropathy Reiter \200\231s disease ENTEROPATHIC SPONDYLARTHROPATHY 230 Enteropathic spondylarthropathy De \201 nition The commonest extra-intestinal manifestations of in \202 am- matory bowel disease (IBD) are musculoskeletal. The condition has been variably referred to as enteric a rthritis, IBD arthropathy, enteric SpA, Crohn \200\231s, or colitis-related arthritis. Key clinical features in ESpA Musculoskeletal \200 \200 \200 \200 \200 \200 \200 In \202 ammatory spinal pain. Alternating buttock pains. Enthesopathy. Anterior chest wall pain. Dactylitis. Peripheral arthritis/arthralgia. Sacroiliitis (most commonly unilateral) . Epidemiology The reports of SpA in IBD have varied owing to de \201 nition of SpA and IBD case ascertainment but have suggested: \200 \200 SpA prevalence of about 20% in IBD patients. Dactylitis, enthesitis, isolated (often asympt omatic) sacroiliitis, and other SpA like lesions all appear to occur in up to 35%. Peripher al arthritis prevalence 5 \200\22320% in IBD. Non musculoskeletal extra-intestinal \200 \200 \200 \200 \200 Aphthous stomatitis. Psoriasis. Erythema nodosum. Uveitis. Urethritis/cervicitis. Etiology and pathophysiology Genetic factors \200 Where AS is clearly de \201 ned in IBD patients, an association with HLA B27 (50 \200\2237 0% patients) clearly exists. HLA B27 frequency may not be increased, however, where there i s peripheral arthropathy alone. Mutations in the CARD15/NOD2 gene confers suscep- tibility for Crohn \200\231s disease, but not AS. Key features in history \200 In patients without a prior diagnosis of IBD, a history of abdominal pain, recurrent diarrh ea (especially at night), fever, malaise/fatigue, and passing blood per rectum is consisten t with a diagnosis of IBD. Aphthous ulceration and fatigue are early IBD features. As with other SpAs, a history of in \202 ammatory spinal pains, buttock or anterior chest wall pai ns or previous insertional tendonitis (enthesitis) might point toward ESpA in patients with established IBD. \200 Environment \200 Intestinal bacteria may have an important role in triggering EspA in Crohn \200\231s diseas e. Compromised iliocaecal integrity is associated with increased musculoskeletal symptoms i n IBD and it has been hypothesized that gut (?luminal/?entero-adhesive) bacteria may play a role in generating arthritis in IBD. Key features on examination Sacroiliitis stress tests (see USpA chapter), and checking for dactylitis and enthesitis are important aspects. Immunopathology \200 Co-morbidities All SpA related features can occur in association with IBD and ESpA (e.g. uv eitis, psoriasis). \200 The immune response in Crohn \200\231s disease suggests CD4 Th1 cells become activated agai nst normal gut luminal bacterial \202 ora. In Crohn \200\231s mucosa there is increased I l-12, Il-6, Il-15, Il-18, TNFA and IFNG with apoptosis-resistant Th1 cells, activated macro phages and granulomata. There \200\231s a paucity of data directly linking enteral immunpat hology with immune processes in joints/entheses in ESpA. IBD-related features can occur and include mouth ulcers, erythema nodosum, pyoderma gangren osum. Bone fragility/osteoporosis is a common complication of IBD. Fracture incidence in IB D is markedly higher than the general population. Hypovitaminosis-D is common in the genera l population, associated with GC use and can lead to myalgia, subopti- mal calcium absorpti on from the gut and secondary hyperparathyroidism (SHPT). Malabsorption in IBD can include folate, B12, and calcium de \201 ciency. The latter causes SHPT. Tissue pathophysiology \200 The peripheral arthritis in IBD has not been adequately characterized to know whether lesio ns are predominantly synovitic or enthesitic. Axial SpA features in ESpA appear similar to lesions seen in other SpAs though this assertion is based on imaging, rather than direct ti ssue studies. Investigations Laboratory The interpretation of acute phase response and anemia requires in terpretation of the activity of any IBD. ESpA symptoms can be prominent with relatively lit tle or absent acute phase response. Clinical features Key clinical features \200 Various subtypes of IBD-related arthropathy have been described. Incomplete case ascertainm ent, suboptimal clinical assessments and insuf \201 cient con \201 rmatory imaging have h ampered clinical pattern recognition studies. A careful review of studies suggests SpA feat ures are consistently conspicuous in IBD patients. USpA can precede a diagnosis of IBD in 5 0% patients. ESpA symptoms and disease activity do not always correlate well with the activ ity of the IBD. Tests to rule out malabsorption may be necessary (e.g. B12, folate). Detailed bone biochemi stry is sensible (calcium, phosphate, ALP, Vit-D, PTH, Mg). Persistent low Vit-D can cause non-speci \201 c musculoskeletal aches. Imaging \200 \200 Pelvis radiographs may show sacroiliitis, osteitis pubis or enthesopathy (although enthesop athic features in ESpA have not been highlighted in the literature). CHAPTER 7 The spondylarthropathies 231 Many radiographic features recognized in ESpA are common to all SpAs. CT may disclose sacro iliitis in about a third of IBD patients; almost twice the detection rate with radio- graph s. Secondary hypertrophic osteoarthropathy is recognized, although unusual in adults and ch ildren with IBD. Azathioprine, although used frequently for severe IBD, and cyclophosphamide, and occasional ly for severe IBD, are not recognized as effective for ESpA. Mesalazine has weak activity a gainst ESpA, and SZP is not as effective for IBD as mesalazine and has more side effects. I f ESpA is the main problem and the IBD in remis- sion, it is reasonable to swap mesalazine for SZP. Current controversies Diagnostic issues \200 Typical features on radiographs in patients with ESpA \200 \200 In early ESpA-sine-IBD, which logically would be classi \201 ed as USpA under ESSG criteri a, are there predictors of the development of IBD? Uncertainty still remains as to the prev alence of ESpA in IBD. For example, SIJ disease is often asymptomatic. What might the preva lence of isolated enthesitis be? The role of MR needs clari \201 cation in early diagnosis of ESpA \200\223 as is the case in other SpAs. General: enthesopathic erosions and enthesophytes. Pelvis: sacroiliitis, osteitis pubis, de structive hip arthritis (symmetric joint space loss, cystic lesions, but distinguish from o steonecrosis). Spine: vertebral squaring; marginal and para-marginal syndesmophytes; discit is. Peripheries: oligoarticular synovitis; radiographic features often lack speci \201 cit y. Management/treatment issues There are no RCTs of SZP or methotrexate in ESpA. The pharmacol ogical management of ESpA is necessarily complicated by the presence of IBD: \200 Discitis presents a diagnostic dilemma. Sterile discitis is a feature of SpAs; however, the re is increased risk of septic lesions in IBD. Imaging features might not always distinguis h. Biopsy should be considered.