Results from the 1958 British Birth Cohort Study. Arth Rheum 2007; 56: 1669-1675. Allison TR, Symmons DPM, et al. Musculoskeletal pain is more gen- eralised among people fro m ethnic minorities than among white people in Greater Manchester. Ann Rheum Dis 2002; 61: 151 \200\2236. Arnold LM, Goldenberg DL, et al. Gabapentin in the treatment of \201 bromy algia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum.2 007; 56: 1336 \200\22344. Arnold LM, Keck PE. Antidepressant treatment of \201 bromyalgia: a Relaxation Relaxation and education programs are less likely to induce improvement in pain, functioning, and mood unless combined with other modalities. meta-analysis and review. Psychosomatics 2000; 41: 104 \200\22313. Arnold LM, Lu Y, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of \201 bromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004; 50: 2974 \200\22384. Complementary therapies There is no good evidence to support any of the comple- mentary the rapies in patients with FMS. Nevertheless, some patients \201 nd complementary therapies helpful for their symptoms. Sadly, most patients who attend such therapies are not informed of potential side effects, the industry remains unregulated and there is uncertainty as to the long-term impact of their interventions. Arnold LM, Rosen A, et al. A randomized, double-blind, placebo- controlled trial of duloxet ine in the treatment of women with \201 bromyalgia with or without major depressive disor der. Pain 2005; 119: 5 \200\22315. Benjamin S, Morris S. The association between chronic widespread pain and mental disorder. A population-based study. Arth Rheum 2000; 53: 561 \200\2237. Carroll D, Seers K. Relaxation for the relief of chronic pain: a sys- tematic review. J Adv Nurs 1998; 27: 476 \200\22387. Prognosis and natural history Only 15% of patients who reported chronic widespread pain in a postal survey reported no pain when the survey was repeated after 7 years. Poorer prognos is was associ- ated with being >50 years old, reporting dry eyes or mouth, and daytime tire dness. Cowan D, Wilson-Barnet J, et al. A randomized, double-blind, placebo-controlled, cross-over pilot study to assess the effects of long-term opioid drug consumption and subsequent abst inence in chronic non-cancer pain patients receiving controlled-release morphine. Pain Med 2005; 6: 113 \200\22321. Crofford LJ, Pillemer SR, et al. Hypothalamic-pituitary-adrenal axis perturbations in patie nts with \201 bromyalgia. Arthritis Rheum 1994; 37: 1583 \200\22392. Current controversies The genetics of pain suggests that many hundreds of genes, if not tho usands are involved suggesting that mechanisms are even more complex than outlined here. Me chanistic- based approaches for helping patients with chronic pain appear some way off. Crofford LJ, Rowbotham MC, et al. Pregabalin for the treatment of \201 bromyalgia syndrome. Arthritis Rheum 2005; 52: 1264 \200\22373. Goldenberg DL. Fibromyalgia and related syndromes. In: Klippel JH, Dieppe PA (eds) Rheumato logy, 2nd edn. New York: Mosby, Section 4.15, 1 \200\22312. G tzsche PC. Reporting of outcomes in arthritis trials measured on ordinal and interval sc ales is inadequate in relation to meta- analysis. Ann Rheum Dis. 2001; 60: 349 \200\22352. Serotonergic descending pathways from the brainstem and midbrain that are thought to be \200\230raising \200\231 the spinal gate to prevent spinal cord sensitization may, in fact, be \200\230lower- ing \200\231 it and cause such central sensitization. Gracely R, Petzke F, et al. Functional magnetic resonance imaging evidence of augmented pai n processing in \201 bromyalgia. Arthritis Rheum. 2002; 46: 1333 \200\22343. Patients with chronic pain have a higher incidence of mortality although this may be accoun ted for by adjusting for smoking and obesity confounders. Hunt IM, Silman AJ, et al. The prevalence and associated features of chronic widespread pai n in the community using the \200\232Manchester de \201 nition of chronic widespread pain . Rheumatology 1999; 38: 275 \200\2239. Resources Guidelines Carville SF, Arendt-Nielsen A, et al. EULAR evidence based recommendat ions for the management of FMS. Ann Rheum Dis 2007. E-pub Oct 3. Jain AK, Carruthers BM, et al. Fibromyalgia syndrome: Canadian clinical working case de \201 nition, diagnostic and treatment protocols \200\223 a consensus document. J Musculo- skel Pain 2003;11: 3 \200 \223107. US-based National Guideline Clearing House, 2005. Available at: http://www.guideli ne.gov/summary/ summary.aspx?doc_id=7352 Kalso E, Streetcar r MR, et al. Systemic local anesthetic type drugs in chronic pain: a systematic review. Eur J Pain 1998; 2: 3 \200\22314. Main CJ, Waddell G. Behavioral responses to examination. A reap- praisal of the interpretat ion of \200\230nonorganic signs \200\231. Spine 1998; 23: 2367 \200\22371. McBeth J, MacFarlan GJ, et al. The association between tender points, psychological distres s, and adverse childhood experi- ences. A community-based study. Arthritis Rheum 1999; 42: 1397 \200\223 404. Papgeorgiou AC, Silman AJ, Macfarlance GJ. Chronic Widespread pain in the population: a sev en year follow-up study. Ann Rheum Dis; 2002; 61: 1071 \200\2234. Russell IJ, Orr MD, et al. Elevated cerebrospinal \202 uid levels of sub- stance P in pat ients with the \201 bromyalgia syndrome. Arthritis Rheum 1994; 37: 1593 \200\2231601. Patient organizations Fibromyalgia Association UK Helpine 0845 345 2322. Available at: www.fibromyalgia-associati onuk.org Arthritis Research Campaign. Available at: www.arc.org.uk See also www.ukfibromyal gia.com; www.myopain.org Tofferi JK, Jackson JL. Treatment of \201 bromyalgia with cyclobenz- aprine: a meta-analysis. Arthritis Rheum 2004; 51: 9 \200\22313. Wolfe F, Smythe Ha, et al. The ACR 1990 criteria for the classi \201 cation of \201 brom yalgia. Report of the Multicentre Criteria Committee. Arthritis Rheum 1990; 33: 160 \200 \22372. ICD-10 codes M79.0; M79.7 References Jones GT, Silman AJ, et al. Are common symptoms in childhood associated with chr onic widespread body pain in adulthood? This page intentionally left blank COMPLEX REGIONAL PAIN SYNDROME TYPE I 488 Complex regional pain syndrome type I Background As common as rheumatoid arthritis this condition affects peripheral and central nervous systems, and all of the tis- sues in the affected limb. The result is intractable p ain, de- formity, loss of function, and even amputation. Clinical features Key features in the history \200 \200 Rule out other causes of syndromes similar to CRPS. Assess for risk factors such as co-morb idities. A large sample of patients meeting IASP criteria for CRPS report: \200 \200 \200 \200 \200 \200 \200 History 1864 Silas Weir Mitchell described causalgia in wounded Color and temperature asymmetry (87%). Spontaneous burning or stinging pain (81%). Hyperaes thesia (61%). Sweating asymmetry (53%). Altered skin (24%). Altered nail growth (21%). Hair growth (18%). soldiers of the US Civil War. 1900 Sudek described localized osteoporosis in the condition. 1947 Evans coined the term \200\230re \202 ex sympathetic dystrophy \200\231. 1959 Curtis s and Kincaid described 3 cases of transient osteoporosis. Other features related to cortical plasticitv may be re- ported by the patient. These might include a change in the perception of their body schema: \200 1994 International Association for the Study of Pain (IASP) recommended the terms Complex r egional pain syndrome (CRPS) type I (no nerve damage) and CRPS type II (nerve damage). Feeling that their affected limb does not belong to them (depersonalization). Lack of aware ness of their affected limb. Feeling of swelling. Desire to get rid of their limb (autotomy -wish). Neglect-like syndrome. De \201 nition CRPS-1 is formerly known as re \202 ex sympathetic dystrophy (RSD) or oste odystrophy. The new de \201 nition requires: \200 \200 \200 \200 \200 An initiating noxious event/immobilization. Spontaneous pain (allodynia/hyperalgesia), disp ropor- tionate to the initiating event and non-dermatomal. Evidence of vascular instability , local changes in growth or function of connective tissues (skin, nails, hair, etc.). CRPS -1 to be a diagnosis of exclusion. Key features on examination Features related to IASP criteria: \200 \200 \200 \200 \200 \200 \200 \200 \200 Mechanical and thermal allodynia (71%). Decreased range of movement (70%). Color asymmetry (66%). Temperature asymmetry (56%). Abnormal sweating (24%). Dystonia (14%). Tremor (9%). H air or nail changes (9%). Skin changes (20%). Features related to cortical plasticitv: Alte red body schema (described with eyes closed). Digit misperception (eyes closed, which \201 nger touched). Parietal lobe dysfunction (neuropsychological tests). Referred sensatio ns (hand-face commonest). Epidemiology 2 population-based studies have been performed. \200 De Mos estimated an incidence of 26 per 100 000 in the Netherlands. Sandroni et al estimate d an incidence of 5 per 100 000 in Minnesota with a period prevalence of 21 per 100 000. as 75% underwent spontaneous resolution. The following characteristics were apparent from the se \200 \200 \200 two studies: \200 \200 \200 \200 7th decade gave the highest presentation. Upper extremity more commonly affected than lower . Female:Male ratio 3 \200\2234:1. Antecedent event (fracture commonest cause \200\223 45% ). Co-morbidities Depression, anxiety and panic disorders, disorders of body image (obesity, e ating disorders). Etiology and pathophysiology Central nervous system changes can be seen and intrigu- ingly reorganize into a more normal pattern when the dis- ease gets better. Thalamic and somatose nsory changes are the most obvious. \200 Differential diagnosis \200 \200 \200 \200 \200 Fracture. Nerve injury. Infection. Vascular insuf \201 ciency (arterial or venous). CNS le sion. Nociceptive loop, whereby noradrenaline release from the sympathetic nervous system activat e nociceptors may propagate peripheral pain. The sympathetic nervous system, autonomic nerv ous system, spinal cord, peripheral \201 bres are all seen to dem- onstrate abnormalities . Peripheral mechanisms for the syndrome, including ischaemia, neurogenic in \202 ammation , and immobilization have been put forward. Psychological factors do not appear to be any d ifferent than other patients who exhibit chronic pain. Investigations As a diagnosis of exclusion, investigations should be tai- lored to rule out infection, in \202 ammation, crystal arthritis, trauma (stress fracture), and osteonecros is or other diag- noses on the differential dependent upon clinical \201 ndings. \200 Venous or lymphatic obstruction or arterial ischaemia can also be confused with CRPS-1. Rou tine blood tests and local radiographs can therefore be helpful. CHAPTER 17 Chronic pain 489 Specialized tests, such as thermography, triple phase radionuclide bone scans and MRI can g ive characteristic appearances, but are neither sensitive nor specific enough to con \201 rm or refute the diagnosis. Psychological treatments Hypnotherapy, imagery, progressive muscle relaxation, au- togenic training, and EMG, or thermal biofeedback all have been used in treating \200\230learned d isuse \200\231. Cognitive approaches may also be helpful. There are no good studies to date . Treatment Objectives of management The overriding aim of management is the functional resto - ration of the affected limb. Prognosis and natural history It \200\231s likely that the majority of patients with CRPS w ill spon- taneously resolve. What propagates the condition in some people is an area for ac tive research. Some people will have many years of intractable pain and disrupted functioni ng. Physical therapies Desensitization and gentle mobilization using occupational therapists an d physiotherapists form the mainstay of treat- ment, and should be supported by nerve block s, medica- tions, and cognitive-behavioral therapy. A multidisciplinary team is therefore e ssential. Current controversies Patients with CRPS are seen to have brain changes in the somatosensor y cortex and changes in the body schema able to be detected clinically. Mechanisms involved in neu- roplasticity are related to the pathophysiology of CRPS and may be therapeutic tar gets of the future. Pharmacological therapies \200 Randomized controlled trials with intravenous clodro- nate and alendronate have demonstrate d that these treatments, as well as intranasal calcitonin, are bene \201 cial for improvin g pain, movement and function. Gabapentin is perhaps the best-studied adjunct treat- ment a nd appears to help patients, although can cause weight gain, light-headedness, and poor con centration. Tricyclic antidepressants may also be useful in CRPS-1, but have more side effe cts than SSRIs. Good trial data for CRPS-1 is lacking. A controlled trial of GCs in a small number of patients demonstrated improved outcome over placebo. Intravenous phentolamine an d other sympatholytic agents, including reserpine, phenoxybenzamine, and clo- nidine have n ot demonstrated ef \201 cacy in small trials, but anecdotally help some patients. Thalidom ide and anti-TNFA agents are being actively studied after case report evidence. Topical cap saicin might be useful, but is painful and dif \201 - cult to apply. Topical lidocaine pat ch may be useful. Topical DMSO, a free radical scavenger, may also be ef \201 - cacious. H igh dose oral vitamin C may work for similar reasons. Using neuropsychological techniques to study differ- ences in patients with chronic pain, a nd healthy volunteers may be a productive method for studying differences in their cognitiv e and emotional responses that can be used for therapies and outcome measures. There may be an autoimmune component as well as an endocrine component to CRPS that may all ow treatment modalities, such as IVIg. Resources Assessment tools Pain assessments (e.g. Brief pain inventory, Short form Mc- Gill ); Functional assessments (e.g. upper extremity func- tional index; lower extremity functio nal index); Health quality (e.g. SF-36); Emotional assessments (e.g. HAD, BDI) Patient organizations UK Patient-led information and links. Available at: www. rsd-crps.co. uk USA websites: www.rsdfoundation.org; www.rsds. org \200 Guidelines American guidelines. Available at: http://www. guidelines.gov/summary Interventional therapies \200 Internet sites RNHRD, Bath inpatient programs. Available at: www. rnhrd.nhs.uk/departments/ rheumatology/complex_ regional_pain_syndrome.htm There is no evidence from existing trials that guanethidine used in intravenous regional sy mpathetic blockade reduces the pain associated with CRPS-1 above that of placebo. Based on a small number of patients, there is weak evi- dence that ketanserin and bretylium may prov ide some relief. Blocks anecdotally may be helpful for patients with mechanical allodynia, and burning pains accompanied with changes in temperature and color, or to help reha- bilit ation that has stalled. There is limited evidence of long-term bene \201 t of spinal cord stimulators from a single randomized trial and a number of case series, and as technology i mproves this may change. Less data exists for spinal cord pumps with morphine, baclofen, cl onidine, or ziconotide, a conotoxin-derived agent. Chemical or surgical sympathectomy also has little good published evidence, and the true risk-bene \201 t balance is dif \201 cul t to establish for this intervention. Deep brain stimulation has been tried, but is not wid ely available or recommended. ICD-10 codes M89.0 Algoneurodystrophy, shoulder-hand syndrome, Sudeck \200\231s atrophy, sympathetic re \202 ex dystrophy. G56.4 Causalgia References Bruehl S, Chung OY. Psychological and behavioral aspects of com- plex regional pain syndrome. Clin J Pain 2006; 22: 430 \200\2237. De Mos M, De Bruijn AG, et al. The incidence of complex regional pain syndrome: a populatio n-based study. Pain 2007; 129: 12 \200\22320. Forouzanfar T, Koke AJ, et al. (2002). Treatm ent of complex regional pain syndrome type I. Eur J Pain 2002; 6: 105 \200\22322. Harden RN, Swan M, et al. Treatment of complex regional pain syndrome. Clin J Pain 2006; 22: 420 \200\2234. Jadad, A. R, Carroll, D, et al. Intravenous regional sympathetic block- ade for pain relief in re \202 ex sympathetic dystrophy: a systematic review and a randomized, double-blind c rossover study. J Pain Symptom Manage 1995; 10: 13 \200\22320. Kingery WS. A critical review of controlled clinical trials for periph- eral neuropathic pa in and complex regional pain syndromes. Pain 1997; 73: 123 \200\22339. COMPLEX REGIONAL PAIN SYNDROME TYPE I 490 Severens JL, Oerlemans HM, et al. Cost-effectiveness analysis of adjuvant physical or occup ational therapy for patients with re \202 ex sympathetic dystrophy. Arch Phys Med Rehabil. 1999; 80: 1038 \200\22343. Shenker NG, Cohen HC, et al. Developing concepts in allodynic Lewis JS, Kersten P, et al. Body perception disturbance: a contribu- tion to pain in comple x regional pain syndrome. Pain 2007; 133: 111 \200\22319. McQuay HJ, Tramer M, et al. A systematic review of antidepressants pain. Clin Med 2008; 8: 79 \200\22382. in neuropathic pain. Pain.1996; 68: 217 \200\22327. Silber T. Eating disorders and reflex sympathetic dystrophy syndrome: is there a common pat hway. Med Hypotheses, 1997; 48: 197 \200\223200. Mellick GA, Mellick LB. Re \202 ex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil 1997; 78: 98 \200\223105. Nelson DV, Stacey BR. Interventional therapies in the management of complex regional pain s yndrome. Clin J Pain 2006; 22: 438 \200\22342. Rowbotham MC. Pharmacologic management of CR PS. Clin J Pain Taylor RS. Van Buyet JP. Spinal cord stimulation for complex regional pain syndrome: a syst ematic review of the clinical and cost-effec- tiveness literature and assessment of prognos tic factors. Eur J Pain 2006; 10: 91 \200\223101. 2006; 22: 425 \200\2239. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex Regional Pain Syndrome type I: incidence and prevalence in Olmsted county. A population-based study. Pain, 2003; 103: 199 -207. van Hilten BJ, van de Beek W-JT, et al. Intrathecal baclofen for the treatment of dystonia in patients with re \202 ex sympathetic dystro- phy. N Engl J Med 2000; 343: 625 \200\2233 0. 491 Chapter 18 Miscellaneous diseases Acromegaly 492 Diabetes mellitus 494 Adult onset Still \200\231s disease 496 Amyloidosis 49 8 Autoin \202 ammatory syndromes 500 Hyperimmunoglobulinaemia D with periodic fever syndro me 502 TNF-receptor-associated periodic syndrome 503 Cryopyrin-associated periodic syndrome 504 Haemochromatosis 506 Haemoglobinopathies 508 Hemophilia 510 Sarcoidosis 512 Panniculit is 514 Alkaptonuria 516 Gaucher \200\231s disease 518 Eosinophilia-myalgia syndrome and tox ic oil syndrome 520 Metabolic myopathies 522 Synovial osteochondromatosis 526 Pigmented vil lonodular synovitis 527 Bone tumors 528 ACROMEGALY 492 Acromegaly \200 Ulnar and popliteal nerves may be enlarged and palpable. Spinal cord compression and cauda equina syndrome are rare. Acromegaly is caused by over secretion of growth hor- mone usually by a pituitary tumor. De \201 nition Acromegaly is caused by over secretion of growth hor- mone usually by a pit uitary tumor, resulting in soft tissue over-growth in adults and gigantism in children. Muscle disease Proximal weakness out of proportion to the increased muscle mass. Decreased exercise tolerance. General investigations Radiological investigations \200 Etiology \200 Acromegaly is usually caused by a benign pituitary tumor (acidophilic tumor), resulting in over-production of growth hormone (GH). Growth hormone stimulates the growth of all tissue, with an increase in protein synthesis. Epiphyseal chondro- cytes proliferate and in adults there is reactivation of chondral proliferation. Excess GH accelerates the aging process a nd increases the occurrence and severity of OA. Cartilage hypertrophy. Widening of the joint space occurs combined with soft tissue and syn ovial hypertro- phy. Most frequently seen in the knees, MCP, and inter- phalangeal (IP) joi nts. Cartilaginous and osseous degeneration. Thickened car- tilage is prone to premature de generation. The earliest sign is the vacuum sign in the knee joints. Small osteo- phytes an d increased joint space are very suggestive of acromegaly. In the terminal phalanges a typi cal feature is the enlarge- ment of the tuft and base of the distal phalange. Clinical features Acromegaly progresses slowly with enlargement of the head, face, hands, a nd feet. Key features on history Musculoskeletal \200 Back pain occurs in 50%, predominately in the lumbar spine. 70 \200\22390% of patients deve lop arthralgia. Neuropathy Parasthesiae and pain in the hand suggestive of carpal tun- nel syndrome is comm on, due to compression and hyper- trophy of the median nerve. Carpal tunnel syndrome occurs in 50% of patients. Myopathy Proximal muscle weakness occurs in 50%. Key features on examination Soft tissue over-growth \200 Characteristic facies \200\223 prominent supraorbital ridge, large nose, prognathism, thic kened lips and tongue. Coarse thickened skin. Increased thickness of the heal pad. Musculoskeletal \200 \200 \200\230Spade-like \200\231 hands due to soft tissue over-growth. Thoracic kyphosis and ri b enlargement leading to barrel chest. Signs of OA: crepitus, loss range of movement, and d eformity of large joints, knees, hips, and shoulders. The \201 rst MCP is typically invol ved. Palpable bursae may be thickened. Neuropathy \200 Signs of carpal tunnel syndrome: median motor and sen- sory impairment, positive Phalen \200\231s and Tinel \200\231s sign. Figure 18.1 Standing plain radiograph of knee, showing early osteoarthritic changes and an increase in joint space. CHAPTER 18 Miscellaneous diseases 493 Differential diagnosis The combination of clinical and radiological features should make th e diagnosis straightforward. In acromegaly, non- weight bearing joints, such as elbows and shoulders are involved unlike primary OA. Hyperostosis may resemble DISH. References Liote F, Orcel P. Osteoarticular disorders of endocrine origin. Baillieres Best Pract Res Clin Rheumatol 2000; 14: 251 \200\22376. Forgacs S. Acromegaly. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M (eds) Rhe umatology, 3rd edn. Ottawa: Mosby 2003 Treatment \200 Treatment is of the primary pituitary tumor. Soft tissue over-growth manifestations are oft en improved by reduction in GH levels. Degenerative hyperostotic manifestations do not impr ove after reduction of GH levels. DIABETES MELLITUS 494 Diabetes mellitus Diabetes mellitus is characterized by chronic hyperglycae- mia this leads to metabolic dysf unction and protein disor- ders. A variety of musculoskeletal disorders occur in long durat ion diabetics. Treatment \200 Conservative management is key with good care of ulcers; a combined approach with a diabeti c foot care team is essential. Surgery should be avoided if possible. Good control of diabe tes is essential both to treat estab- lished disease, and also to prevent developvment of l ate complications of diabetes such as neuropathy and oste- oarthropathy. Diabetic osteoarthropathy This is a late complication of diabetes mellitus, occurring in up to 1.4% of diabetics predominately in the over 50 years of age group. It affects predominately the foot joints, with the MTPJs Diabetic cheiroarthropathy Most commonly occurs in long-standing type I diabetics. most commonly involved. Clinical features Key features on history The pain is much less severe than expected becaus e neu- ropathy is always also present. \200 Clinical features Key features on history \200 Parasthesiae and pain are the earliest features, which progresses very slowly. Loss of hand function. Musculoskeletal: swelling of the foot joints that is rela- tively painless. Neurological: p arasthesiae and numbness. Cutaneous: ulcer formation. \200 Key features on examination \200 Thick, tight waxy skin. \200 Joint restriction and scl erosis of tendon sheaths. \200 Typical prayer sign with the patient unable to press the h ands together. Key features on examination \200 Musculoskeletal: increased joint mobility due laxity of the joint capsule. Soft tissue swel ling: metatarsal joint destruction with foot shortening, collapse of the medial arch led to devel- opment of the \200\230rocker bottom foot \200\231. Neurological: sensory neuropath y, loss of vibration sense and decreased re \202 exes. Cutaneous: neuropathic plantar ulce rs occur in associa- tion with bone destruction. Pathogenesis Diabetic microangiopathy is thought to be the main factor. Treatment There is no speci \201 c treatment apart from good diabetic control, analgesia a nd symptomatic management. Diabetic femoral amyotrophy \200 Diabetic femoral amyotrophy is characterized by severe unilateral anterior thigh pain follo wed by wasting and weakness of quadriceps muscles and loss knee re \202 ex. It is bilatera l in 50% of patients. Recovery begins at 3 months and is usually complete by 18 months. Radiological investigation Plain radiology is the best means of making the diagnosis. Three stages can be identi \201 ed on plain radiographs Porosis, cortical defects, and subluxat ion. Osteolysis, fragmentation, fractures, periosteal reaction. Cortical defect \201 ling , deforming arthritis, ankylosis. MRI is useful for distinguishing diabetic osteoarthropath y \200 \200 Muscle infarction \200 from osteomyelitis. Muscle infarction is a rare cause of severe pain in diabet- ics. There is acute severe pain and swelling of muscle, typically the thigh. Muscle biopsy shows necrosis and oedema. Reso lution occurs over a few weeks, but recurrence is common. Differential diagnosis Diabetic osteoarthropathy must be distinguished from in- fection, os teoarthritis, other neuropathic arthropathies, tumors, and in \202 ammatory arthritis. \200 Pathogenesis \200 References Liote F, Orcel P. Osteoarticular disorders of endocrine origin. Neuropathy is the major cause of osteoarthropathy and the osteolysis is due to neurogenic f actors and not in \202 ammation. Infection and microangiopathy play a less signi \201 can t role. Baillieres Best Pract Res Clin Rheumatol 2000; 14: 251 \200\22376. Prognosis Osteolysis may stop spontaneously with healing. This page intentionally left blank ADULT ONSET STILL \200\231S DISEASE 496 Adult onset Still \200\231s disease \200 \200 De \201 nition Adult onset Still \200\231s disease (AOSD) is a rare condition char- acteri zed by recurrent episodes of in \202 ammation. Sore throat occurs in up to 92% of cases. Weight loss of > 10% occurs in 75%. Lymphadenopat hy occurs in 65%. Hepatosplenomegaly occurs in 50%. Diagnostic criteria There are several sets of diagnostic criteria of which the Yamaguchi ar e the most sensitive (93.5%). Musculoskeletal \200 Joint pain is a common feature and is greatest during febrile episodes It becomes worse d uring the course of illness and may be very mild at presentation. Myalgia (75%) can be seve re and also increases during febrile episodes. Abdominal pain is usually mild and infrequen tly severe enough to warrant laparotomy. Pleurisy and pericarditis occur in 30 \200\22340% of patients. Yamaguchi criteria for Adult onset Still \200\231s disease Major criteria \200 Arthritis. \200 Swelling or limitation of motion, warmth, pain, stiffness. \200 Duration of 6 wee ks. \200 Exclusion other reasons for arthropathy. \200 Fever (>39.0 C) persisting, int ermittent. \200 Typical rash: persistent eruption is NOT characteristic of the disease. E levated WBC > 10 000. Key features on examination Musculoskeletal \200 Initially the synovitis is migratory and additive, but becomes more persistent. This can in volve both large and small joints (both PIPJ and DIPJ of the hands), with the knee being mo st commonly involved (84%). The axial skeleton is infrequently involved. Minor criteria \200 Sore throat. \200 Lymphadenopathy or splenomegaly. \200 Abnormal LFTs \200\223 not attributable to drug toxicity or allergy. Negative ANA or RF. Skin \200 The rash is characteristically salmon pink, macular, or maculopapular. It is evanescent and occurs during febrile attacks lasting for several hours. Lymphadenopathy (65%) most common ly occurs in the cervical region, the nodes are mobile and tender. Exclusion criteria Infection, malignancy, vasculitis. To establish a diagnosis of AOSD, patients require \201 ve criteria including two major c riteria. From Yamaguchi et al. (1992). General investigations The diagnosis is often delayed due to the non-speci \201 c na- ture of the illness. \200 Epidemiology \200 \200 \200 FBC anemia of chronic disease, leucocytosis (WBC>15 x 109/l in 80%), thrombocytosis. Acute phase response (ESR and CRP) is raised in all patients. Liver function abnormal in 75%. Fer ritin: hyperferritinaemia with extreme elevation is common. It is unrelated to iron metabol ism and is due to cytokine-induced increased synthesis by the reticulo- endothelial system. The incidence is 1 \200\2232/million/year. Sex distribution is equal. The peak age of onset is 16 \200\22335 years. \200 Etiology \200 The etiology is unknown, but the clinical presentation with fever, rash, sore throat, and l ymphadenopathy sug- gests an infectious cause. A viral etiology has most often been suggest ed, but no agent has yet been identi \201 ed. There is no clear association with HLA or ot her genetic markers. No clear environmental factors have been found. Pro-inflammatory cytok ines, such as IL-1, Il-6, IL-18, interferon gamma, TNF, and macrophage colony stimu- lating factor are raised, and thought to have role in the pathogenesis. Serological investigations \200 ANCA, ANA, RF, anticardiolipin antibodies. These are usually negative. Complement levels ar e normal. Cryoglobulins. \200 Synovial \202 uid Synovial \202 uid is in \202 ammatory with raised white cell count. Clinical features AOSD affects many organs. The full spectrum of clinical features may not be present at onset and only may develop over a few weeks. Biopsy Lymph node and skin biopsy are not needed for the diag- nosis, but is often performe d to exclude malignancy or vasculitis. Key features on history Systemic \200 Differential diagnosis \200 Fever is almost universal with virtually all patients exhib- iting a fever > 39 C, spiking usually during the evening or night. The differential diagnosis is broad and the diagnosis is essentially that of exclusion. Gra nulomatous disorders, vasculitis, infection, malignancy, and connective tissue disease all need to be ruled out. CHAPTER 18 Miscellaneous diseases 497 Chronic polyarthritis is managed with low dose oral cor- ticosteroids. Immunosuppressive ag ents, such as meth- otrexate, may have a place in reducing steroid exposure and preventing long-term joint damage. Other immuno- suppressive drugs that have been utilized include aza thi- oprine, le \202 unomide, ciclosporin, and cyclophosphamide. Other agents used experim entally include intravenous gamma globulin, inhibitors of TNF-alpha, IL-1, and Il-6. Schnitzler syndrome is rare, but shares many features with AOSD, including high fever, lymp hadenopathy, hepatosplenomegaly, raised acute phase response, and leucocytosis. However, th ere is urticaria and a mono- clonal IgM gammopathy and less marked elevation in ferritin. Prognosis \200 The course is monophasic in 61.5% of cases and relaps- ing in 38.5%. The median duration of treatment is 10 years. Chronic articular involvement occurs in one-third. Presence of poly arthritis especially shoulder or hip joint early in the disease course is predictive of a c hronic course. Death is uncommon, but is due to infection, hepatic failure, and disseminate d intravascular coagulation. Follow-up Every 3 \200\2236 months as patients condition dictates. AOSD is a relapsing cond ition and lifelong follow-up is required. \200 Resources Guidelines There are no guidelines speci \201 cally for AOSD, but refer- ence sh ould be made to local guidance on steroid induced osteoporosis, use and monitoring of immun osuppressive therapy and vaccination. Pathology \200 Lymph node histology shows in \201 ltrates of plasma cells, and polymorphonuclear leucocyt es and reactive hyper- plasia. Skin biopsy shows a mild perivascular in \202 ammation of t he super \201 cial dermis with few lymphocytes or neu- trophils. Liver biopsy mononuclear sinusoidal and portal tract in \201 ltrates with mild Kupffer cell hyperplasia. Focal hepa - titis is less common. Patient organizations International Still \200\231s Disease Foundation. www.stillsdisease.o rg ICD-10 coding M06.1 Adult-oset Still \200\231s disease. References Efthimiou P, Kontzias A, Ward CM, Ogden N. Adult-onset Still \200\231s dis- ease : can recent advances in our understanding of its pathogene- sis lead to targeted therapy. Nat Clin Pract Rheumatol 2007; 3: 328 \200\22335. Patient advice \200 \200 Diagnosis of exclusion. Requires long-term therapy, but in general the prognosis is good. Esdaile JM. Adult Still \200\231s disease. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M (eds) Rheumatology, 3rd edn. Ottawa: Mosby, 2003: 793 \200\22380. Kadar J, Petrovicz E. Adult-onset Still \200\231s disease. Best Prac Res Clin Treatment \200 \200 Rheumatol 2004; 18: 663 \200\22374. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classi \201 cation of a dult-Still \200\231s disease. J Rheumatol 1992; 19: 424 \200\22330. There are no randomized controlled trials in AOSD. Often, in the \201 rst instance, aroun d 20 \200\22325% of patients respond well. Aspirin is often still used in relatively high d oses. Oral corticosteroids usually give quick symptom relief. 0.5 \200\2231.0 mg/kg may be required initially. Pulse intravenous corticosteroids are not usually needed. Depending on response the dose may be tapered quite quickly AMYLOIDOSIS 498 Amyloidosis De \201 nition The amyloidoses are a group of disorders characterized by deposition of ext racellular amyloid \201 brils. which is synthesized by hepatocytes stimulated by pro- in \202 ammatory cytokines. Prolong ed over synthesis of SAA is a requirement for development of AA amyloido- sis, but why only a small proportion of patients with chronic in \202 ammation develop amyloidosis is unkno wn. In the AL type, the precursor is Ig light chain ( or ), light chains are more am yloidogenic. Structural changes in the light chain may be responsible for amyloidogenesis, either deletions resulting in small chains or glycosylation. In A \2372-microglobulin amylo idosis, the precursor protein is \2372-microglobulin. Improved haemodialysis techniques ha ve reduced the frequency of this complication. Epidemiology AA type The most common type of systemic amyloidosis world- wide is AA type. T he most common associations in West- ern countries are chronic in \202 ammatory conditions , whilst in regions where infection is common it is associated with tuberculosis and lepros y (Table 18.1). The reported fre- quency of AA amyloidosis in in \202 ammatory disease var ies widely across the world is probably dependent on the means of diagnosis. Clinical features Key features on history General Symptoms suggestive of amyloidosis includ e proteinuria especially developing in the context of chronic in \202 amma- tory disease o r infection. In a recent series of AA amyloid the mean duration of symptomatic in \202 amm atory disease before development of amyloidosis was 17 years (Lach- mann et al, 2007). The clinical features of AA amyloid are the same irrespective of the underlying in \202 ammato ry disease. AL type In the USA, AL type is most common, the incidence in Olmsted County was estimated t o be 1/100 000 between 1950 and 1989. In Holland, the prevalence is 1/75 000. 20% of people with multiple myeloma develop AL amyloidosis. A \2372-microglobulin A \2372-microglobulin amyloidosis occurs in chronic haemodi- alysis. Etiology \200 Musculoskeletal \200 Amyloid deposition re \202 ects a conformational change in the structure of the precursor protein and is the \201 nal common endpoint of several different processes. There are at least 23 amyloid precursors. A common fea- ture is a B-pleated sheet either in the native p rotein or after conformational change, which is deposited, and dis- rupts the organization and function of tissues and organs. In the AA type the \201 brils are derived from the ac ute phase protein serum amyloid A (SAA) through a process of cleavage, misfolding and aggre gation into a highly ordered abnormal B-sheet conformation. SAA is an apolipoprotein consti tuent of high-density lipoprotein, In AL type amyloidosis joint involvement is infrequent. Joint stiffness occurs more than pa in. Involves both large and small joints either in a symmetrical or asymmetrical manner. A \2372-microglobulin amyloidosis occurs in the setting of chronic dialysis. Always involves the joints and skeleton. There is in \201 ltration of the carpal ligament leading to sympt oms of carpal tunnel syndrome, which in this set- ting should prompt investigation for amyl oidosis. Neck pain is due to a destructive spondyloarthropathy. Musculoskeletal involvement is not a feature of familial transthyretin amyloidoses, but neuropathic joints can develop due to the severe neuropathy. Renal disease Renal disease is the typical presentation of AA (97% at presentation) and AL amyloidosis. Development of pro- teinuria in a patient with longstanding active in \202 am matory disease should prompt investigation for AA amyloidosis. Table 18.1 Associations of AA amyloidosis In \202 ammatory arthritis (60%) \200 Rheumatoid arthritis (most common worldwide (33%)) Juvenile idiopathic arthritis (17%) Neuropathy A sensorimotor proximal or distal polyneuropathy is the presenting feature in 10 \200\22320% of AL amyloidosis. Occurs in the familial TTR amyloidoses Others including ankylosing spondylitis (10%) Chronic Infection (15%) \200 Bronchiectasis (5%) Cardiac Cardiac involvement occurs in 20% of AL patients, but is much rarer (<10%) in AA am yloidosis, and results in a car- diomyopathy and arrhythmias. Injection drug abuse (4%) Complication paraplegia (ulcers etc) (2%) Osteomyelitis (1%) Tuberculosis (1%) Key features on examination Musculoskeletal \200 Periodic fever syndromes (9%) \200 \200 Familial Mediterranean fever (5%) In AL amyloidosis there is stiffness of joints with little swelling. In \201 ltration of t he skin may produce palpable pads e.g. over the shoulders. A \2372-microglobulin. Stiff pai nful peripheral joints with a destructive arthropathy, most common sites are wrist, shoulde rs, hips, knees, and spine. TNF-receptor-associated periodic fever syndrome (2%) In \202 ammatory Bowel Disease (5%) Malignancy (1%) Percentages from a series of 374 patients (Lachmann et al., 2007). CHAPTER 18 Miscellaneous diseases 499 Neuropathy \200 Synovial \202 uid The synovial \202 uid is characteristically non-in \202 ammatory and may contain amyloid \201 brils.