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. Proximal and distal sensorimotor neuropathy. Autonomic neuropathy may occur with postural h ypotension, and incontinence. Neuropathy is not seen in AA amyloidosis. Signs of carpal tun nel syndrome especially in A \2372- microglobulin amyloidosis. Differential diagnosis This is from other causes of nephrotic syndrome or neu- ropathy. Dru gs particularly gold and penicillin may cause proteinuria. General investigations There are no speci \201 c serological or urine markers of amy- loid osis. CRP, SSA, and other acute phase reactants are not speci \201 c markers, as they are raised in chronic in \202 ammation and most patients with chronic in \202 ammation do not de- velop amyloidosis. \200 Pathology Samples for assessment of possible amyloidosis should be stained using Congo red and examined under polarizing light microscopy. Amyloid \201 brils will have apple green bire- fringence. Assessment of renal function with quanti \201 cation of pro- teinuria (nephrotic range > 3 g/24 h). Hypoproteinaemia supports a diagnosis of nephrotic syndrome. Serum and urine immu nofixation, serum-free light chains. The presence of monoclonal Ig or free light chains sug gests AL amyloidosis. Bone marrow aspiration may be required to demon- strate monoclonal pl asma cell proliferation and produc- tion of free light chains. Investigations for hereditar y forms of amyloidosis \200\223 mutations in genes encoding for transthyretin, \201 brin ogen A -chain, apolipoprotein A-I, apolipoprotein A-II, and lysozyme. Treatment \200 AA amyloidosis: the treatment is to control the under- lying in \202 ammatory condition or chronic infection. With treatment regression of amyloid deposits can be observed using ser ial SaP scanning. AL amyloidosis: the aim is to reduce production of amyloid forming monocl onal light chain by treatment of the underlying plasma cell dyscrasia. Prognosis \200 \200 The median survival in AA amyloidosis is 133 months. Factors associated with a poor prognos is are age at presentation and end-stage renal failure. Biopsy Rectal biopsy or subcutaneous fat aspiration are the tech- niques of choice for obta ining tissue for diagnosis. Resources Patient organizations Amyloidosis support network. www.amyloidosis.org. Imaging X-ray Plain radiographic features of amyloidosis include osteopo- rosis, lytic lesi ons, pathological fractures, osteonecrosis, subchondral cysts and erosions. ICD-10 coding E.85 Amyloidosis References Buxbaum J. Amyloidosis. In: Hochberg MC, Silman A, Smolen JS, Weinblatt M, Weism an MH (eds) Rheumatology. Ottawa: Mosby, 2004: 2015 \200\22325. Ultrasound US may show thickening of soft tissues around joints and especially in the wrist . Comenzo RL. Current and emerging views and treatments of sys- temic immunoglobulin light-ch ain (Al) amyloidosis. Contrib Nephrol 2007; 153: 195 \200\223210. MRI \200 MRI may show thickened synovium and soft tissue in \201 l- tration. MRI is the method of c hoice for investigating possible amy- loid deposits, especially in A \2372-microglobulin am yloidosis. Kiss E, Keusch G, Zanetti M, et al. Dialysis-related amyloidosis revis- ited. Am J Res 2005; 185: 1460 \200\2237. Lachmann HJ, Goodman HJ, Gibertson JA, et al. Natural history and outcome in systemic AA am yloidosis. N Engl J Med 2007; 356: 2361 \200\22371. Nuclear medicine Serum amyloid P (SaP) scanning uses iodinated SaP that binds to amyloid \201 brils. It is useful in demonstrating the extent of amyloid deposition and can be used to measure response to treatment. See also Rheumatoid arthritis Autoin \202 ammatory syndromes. AUTOINFLAMMATORY SYNDROMES 500 Autoin \202 ammatory syndromes Clinical features Key features on history \200 The autoin \202 ammatory syndromes are a group of inherited conditions characterized by in \202 ammation, arthralgias, and a propensity for development of secondary AA amyloidosis. The acute attacks of FMF are characterized by fever, serositis, rash, and arthralgia. The d uration of attacks is 24 \200\22372 h, but joint pain can last for 1 week. Attacks are not truly periodic, but can occur at widely varying intervals and, thus, are episodic. There is often no obvious precipitant, but emotion, exer- cise, and menstruation have all been asso ciated. Between attacks patients are asymptomatic. The conditions include: familial Mediterranean fever (FMF), hyperimmunoglobulin D with peri odic fever syn- drome (HIDS), tumor-necrosis factor (TNF)-receptor- associated periodic syn drome (TRAPS), cryopyrin associ- ated periodic syndrome (CAPS). They are distinguished from systemic onset JIA in the child because children are usually well between attacks. The con ditions are all very rare and are best investigated at specialized centers. Systemic The height of the fever varies between patients, but is higher in children. Familial Mediterranean fever Classi \201 cation criteria The Tel Hashomer criteria are wid ely used to clinically de- \201 ne FMF. Cutaneous Tender red plaques on the legs. Serosal \200 Tel Hashomer criteria for FMF Major criteria \200 Abdominal pain is the second most common feature and occurs in >90%. Pleurisy is common and often occurs with abdominal pain. Sharp, stabbing chest pain, worse on inspiration, coughi ng. Pain may be referred to the shoulder from the diaphragm. Pericardial chest pain is unco mmon. Recurrent febrile episodes accompanied by peritoni- tis, synovitis or pleuritis Amyloidosis of the AA-type without predisposing disease Favorable response to colchicine treatment Minor criteria \200 \200 \200 Musculoskeletal \200 Recurrent febrile episodes Erysipelas like erythema FMF in a \201 rst degree relative Arthralgias with or without joint swelling present initially in childhood. Most frequently, monarticular, typically involving the knee or ankle. Polyarticular or oligoarticu- lar pre sentations are less common. Prolonged episodes of myalgia can develop in associa- tion with fever (protracted febrile myalgia); and are thought to be due to vasculitis. De \201 nitive diagnosis: 2 major or 1 major and 2 minor. Probable diagnosis: 1 major and 1 minor. The speci \201 city in a Jewish population is > 95%. Key features on examination Cutaneous The most characteristic lesion is a tender erythemato us plaque on the dorsum of the foot, ankle, or calf. Epidemiology \200 \200 Autosomal recessive condition Most frequent in individuals of non-Ashkenazi Jewish, Armenia n, Arab, or Turkish ethnic origin. Relatively common amongst non-Ashkenazi (Eastern Europea n) Jews and Italians. Carrier frequencies of 1:3 and 1:5 have been reported in some populat ions. Musculoskeletal \200 In \202 ammatory synovitis most commonly affecting the lower limb joints, in a monarticula r pattern. The effusion may be quite large. Destructive arthritis rarely occurs. Etiology Molecular genetics The FMF gene, MEFV, is located on the short arm of chro- mosome 16p13.3 and is a 10-exon gene encoding pyrin a 781 amino acid protein. Serosal \200 Diffuse abdominal tenderness, which may be suf \201 ciently severe to mimic an acute abdom en. Signs of a pleural effusion may be present. Pericarditis is uncommon. \200 There are 4 common missense mutations \200\223 substitution of isoleucine for methionine a t codon 680 (M680I); valine for methionine at 694 (M694V); of isoleucine for methio- nine a t codon 694 (M694I); alanine for valine at 726 (V726A), but over 100 variants have been des cribed. General investigations Investigation is directed at establishing the diagnosis. \200 FBC anemia (only if severe GI or renal hemorrhage), leucocytosis. Acute phase response. The ESR, CRP, serum amyloid A (SAA), \201 brinogen, and haptoglobin are all raised. The MEFV gene produces a pyrin and is expressed in myeloid cells. Pyrin is believed to regu late in \202 ammation by via apoptosis. Mutated variants of pyrin are unable to regu- late in \202 ammation especially pathways involving IL-1B and NFkB. Serological investigations \200 ANA, ANCA, RF should all be negative. A positive ANA or ANCA suggests the presence of a con nective tissue disease or other vasculitis. Complement levels are normal. CHAPTER 18 Miscellaneous diseases 501 Colchicine prevents acute in \202 ammatory attacks and also the long-term development of a myloidosis. Glucocorticoids appear to be ineffective. Anecdotal reports describe successful use of TNF-alpha blockade and Anakinra in colchicine resistant cases. Genetic screening Patients with typical clinical features should be screened for the common mutations (see above) \200 Differential diagnosis The diagnosis is based on clinical manifestations. Patients with typ ical clinical features may not have demonstrable mutations. Since the advent of genetic scr eening patients with milder features are being discovered who do not ful \201 l recognized criteria. Follow-up Long-term follow-up is required with regular urinalysis is necessary to detect de velopment of amyloidosis. Resources Internet resources OMIM 249100 www.ncbi.nlm.nih.gov/entrez/ Prognosis \200 Overall prognosis is determined by the risk of develop- ment of AA amyloidosis. The risk of amyloidosis varies between mutations with the risk apparently highest for patients with th e M694V mutation. A family history of amyloidosis also increases the risk suggesting that o ther genes are important including the SAA1 a/a genotype. ICD-10 code E85.0 Non-neuropathic heredofamilial amyloidosis. Familial Mediterranean fever References Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Me diterranean fever. Arthritis Rheum 1997; 40: 1879 \200\22385. Ozel AM, Demit rk L, Yazgan Y, Avsar K, G nay A, G rb z AK et al. Familial Mediterranean fever: a review of the dise ase and clinical and laboratory \201 ndings in 105 patients. Dig Liver Dis 2000; 32: 504 \200\2239. Patient advice \200 Recessively inherited condition. Recurrent attacks of abdominal pain, fever, and joint pain . Amyloidosis is the most serious complication. Yao Q, Furst D. Autoin \202 ammatory diseases: an update of clinical Treatment \200 and genetic aspects. Rheumatology 2008; 47: 946 \200\22351 Colchicine (1 \200\2232 mg/day) is the basis of treatment. The dose is limited by gastroint estinal side effects \200\223 diar- rhoea, cramping, and bloating. HYPERIMMUNOGLOBULINAEMIA D WITH PERIODIC FEVER SYNDROME 502 Hyperimmunoglobulinaemia D with periodic fever syndrome HIDS is characterized by recurrent attacks similar to FMF, but with the presence of raised levels of IgD in serum. Mucocutaneous \200 Crops of erythematous red macules 0.5 \200\2232.0 cm in diam- eter are the most common feat ure. Painful aphthous orogenital ulcers are sometimes found. Hepatosplenomegaly is seen. Epidemiology A rare condition, most pedigrees are clustered in northern Europe. \200 General investigations \200 \200 Etiology Molecular genetics HIDS is a recessively inherited condition de \201 ned by muta- tions in the mevalonate kinase gene (MVK) located at 12q24, which catalyzes the conversion of mevalonic acid to 5-phosphomevalonic acid, a key stage in the biosynthesis of cholester ol and isoprenoid. The most common mutation is a substitution of isoleucine for valine at c odon 377 (V377I). The exact mechanism is uncertain, defective apoptosis of lymphocytes may be important, and the role of raised IgD is unknown. IgD can increase TNF-A and IL-1 levels . FBC leucocytosis with left shift. Acute phase response. The ESR, CRP, serum amyloid A (SAA) , \201 brinogen and haptoglobin are all raised. Serum IgD elevation > 14.1mg/dl on two oc casions at least 1 month apart. Urine mevalonic acid levels are raised during attacks Genet ic screening Mutational analysis initially looking for the most com- mon mutations V377I or I268T mutations. If this is negative a more comprehensive genome screen can be conducted. \200 \200 Clinical features Key features on history \200 \200 Differential diagnosis This is from the other autoin \202 ammatory conditions. Some patien ts have MVK mutation, but normal IgD levels and are termed variant HIDS. The median age of onset is <6 months. Vaccinations may trigger attacks, as well as infectio ns, emotion, trauma, and surgery. The usual length of attacks of high fever is 3 \200\2237 days. The interval between attacks is variable, but typically 4 \200\2236 weeks. Prognosis Unlike the other autoin \202 ammatory syndromes amyloidosis has not been reporte d in HIDS. The frequency and severity of attacks tend to diminish with age. Serosal The majority of patients have attacks of abdominal pain, which may be severe enough to require laparotomy. Diarrhea is seen more frequently than in FMF. Treatment There is no proven treatment. NSAIDs may control fever and joint pain. Corticoste roids may help some patients. Colchicine is ineffective. Musculoskeletal \200 70% of patients experience arthralgias, with knees and ankles most commonly involved. Attac ks may be polyarticular in contrast to FMF. Resources Internet resources OMIM 260920 www.ncbi.nlm.nih.gov/entrvez/ Key features on examination Lymphadenopathy Widespread, tender lymphadenopathy is more comm on in HIDS than the other autoin \202 ammatory syndromes. Swell- ing varies with attacks. References Drenth JP, Haagsma CJ, van der Meer JM. Hypergammaglobulinae- miaD and periodic fever syndrome. Medicine (Baltimore) 1994; 73: 133 \200\22344. Musculoskeletal Large joint arthritis varying with severity of the febrile epi- sode and wi th abdominal pain. Yao Q, Furst D. Autoin \202 ammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946 \200\22351. CHAPTER 18 Miscellaneous diseases 503 TNF-receptor-associated periodic syndrome TRAPs comprise a group of dominantly inherited fever syndromes, which were previously known under a variety of terms including, e.g. familial Hibernian fever. The discov- ery of the genetic basis led to the syndromes being linked, being due to mutations in the 55 Kd recept or for TNF-A. Ocular 8% of patients experience conjunctivitis, periorbital oedema, and or periorbital pai n. Iritis and uveitis are less common. General investigations \200 FBC leucocytosis with left shift. Anemia of chronic disease. Acute phase response. The ESR, CRP, serum amyloid A (SAA), \201 brinogen and haptoglobin are all raised. Polyclonal inc rease in gamma globulins. Mevalonic aciduria. Epidemiology The original pedigrees were described in Hibernian families, but a broad ethni c distribution has since been described. \200 The condition is inherited as an autosomal dominant. Etiology Molecular genetics TNF- has two receptors a 55kDa molecule (p55) and a 75kDa mol ecule (p75). The p55 receptor is encoded by TNFRSF1A on chromosome 12p13.2, whilst the p75 recep- tor is encoded by TNFRSF1B on chromosome 1p36.3-p36.2. The p55 receptor is expressed on a wide variety of cell types, whilst the p75 is restricted to leucocytes and en- dothel ial cells. TRAPs is caused by mutations in TNFRSF1A. The most frequent mutation is R92Q. Le vels of TNFRSF1A protein is low in plasma and the aberrant form of TNFR1 is present on cell surface. Neutralization of TNF- A is impeded and TNF-A driven in \202 ammation is uncon- trolled. However, the precise pathogenesis of the clinical features is not completely under stood. Serological investigations \200 ANA, ANCA, RF should all be negative. A positive ANA or ANCA suggests the presence of a con nective tissue disease or other vasculitis. Complement levels are normal. Genetic screening Mutational analysis initially looking for the most common mutations. Differential diagnosis This is from the other autoin \202 ammatory conditions. The diagnos is is made by establishing a mutation in TNFRSF1A in a patient with an unexplained fever sy ndrome. Prognosis 14% of patients develop AA amyloidosis. Clinical features \200 \200 The median age of onset is 3 years. The duration of attacks is longer than for the other sy n- dromes lasting longer than 1 week. Treatment \200 Colchicine is ineffective in preventing the febrile attacks and also it does not prevent am yloidosis. Glucocorticoids can be used to treat acute attacks. Etanercept has been used wit h mixed results, but is con- sidered useful as a steroid sparing agent. \200 Serosal \200 \200 \200 Abdominal pain and serositis may be severe. Pleurisy with chest pain occurs. Scrotal pain d ue to in \202 ammation of the tunica vaginalis occurs but uncommonly. Resources Internet resources OMIM 142680 www.ncbi.nlm.nih.gov/omim Musculoskeletal \200 Arthralgia is more frequent than arthritis occurring in two-thirds of patients. Usually non -erosive, and monar- ticular or oligoarticular. Myalgia occurs frequently, unlike FMF. Ther e is a region of muscle pain, which is warm and tender. There is an overlying area of eryth ema which blanches with pres- sure. Biopsy shows a panniculitis, fasciitis and perivascu- l ar in \202 ammation, but no myositis. References Dod C, Andr M, Bienvenu T, Hausfater, P cheux C, Bienvenu J, et al. The enl arging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associa ted periodic syndrome. Arthritis Rheum 2002; 46: 2181 \200\2238. Yao Q, Furst D. Autoin \202 ammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946 \200\22351. CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME 504 Cryopyrin-associated periodic syndrome The cryopyrin associated periodic syndrome (CAPS) is a group conditions previously consider ed to be separate en- tities, but recently shown to be due to mutations in the CIAS1 gene. The group includes Muckle Well syndrome (MWS), familial cold in \202 ammatory condition (F CAS), and neonatal onset multi-system inflammatory disease (NOMID)/chronic infantile neurol ogical cutaneous and articular syndrome (CINCA). Musculoskeletal Arthralgias are more common and affect predominately large joints. The patt ern is typically oligoarticular. Cutaneous The rash is erythematosus geographical plaque, reminis- cent of urticaria, but th ey do not itch. They \200\230ache \200\231. Sensorineural hearing loss \200 MWS is characterized by attacks of fever, malaise, 70% of cases with MWS develop progressive sensori neural hearing loss. Deafness also occurs in CINCA/NOMID. arthralgias, and urticaria. Epidemiology \200 A rare condition, the initial cases were all described in Europe. The inheritance is autoso mal dominant. General investigations \200 \200 FBC leucocytosis with left shift. Acute phase response. The ESR, CRP, serum amyloid A (SAA) , \201 brinogen, and haptoglobin are all raised. Etiology Molecular genetics CAPS is caused by mutations in the CIAS1 gene located on chromo some 1q44. The encoded protein is cryopyrin and >40 mutations are known. The CIAS1 gene pro duct cryopyrin (also known as PYPAF1 or NALP3) is part of the in \202 ammasome and is esse ntial for activation of caspase 1 and processing of IL-1 and IL-18. Thus, the effects of mu tations may be mediated by their effects on IL-1, IL-18, and NFkB. Genetic screening Mutational analysis initially looking for the most common mutations. Differential diagnosis This is from the other autoin \202 ammatory conditions. Prognosis 25% of patients develop AA amyloidosis. Treatment \200 Clinical features Key features on history and examination \200 \200 \200 There is no proven treatment. NSAIDs may control fever and joint pain. Corticosteroids may help some patients. Therapy targeting the IL-1B pathway with IL-!ra (anak- inra) have been effective in a small number of patients. The age of onset is variable from infancy to adolescence. Attacks last 12 \200\22348 h. FCA S is the mildest syndrome. CINCA/NOMID is the most severe. Table 18.2 Major discriminating features of the auotin \202 ammatory condition FMF TRAPS HIDS CAPS Age of onset <20 years <20 years Median 6 months <6 months Fever duration 1 \200\2233 days > 7 days 3 \200\2237 days 1 \200\2232 days Serositis Musculoskeletal Monarthritis Monarthritis, myalgia Polyarthritis Deforming arthritis Cutaneous Erysipeloid Erysipeloid Macules, papules, urticaria Urticaria Adenopathy Rare Rare Yes Rare Deafness No No Dominant No Yes Amyoidosis Inheritance Recessive Recessive Dominant Gene mutation MEFV TNFRSF1A MVK CIAS1 Gene product Pyrin/marenostrin TNFR1A Mevalonate kinase Cryopyrin Therapy Colchicine \200\223 \200\223 \200\223 Glucocorticoids TNF-A blockers IL-1 antagonists \200\223 \200\223 \200\223 \200\223 \200\223 Adapted from Yao & Furst (2008). CHAPTER 18 Miscellaneous diseases 505 Resources Internet resources OMIM 191100 www.ncbi.nlm.nih.gov/omim References Aksentijevich I, Putnam C, Remmer EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients a nd a new cryopy- rin model. Arthritis Rheum 2007; 56: 1273 \200\22385. Yao Q, Furst D. Autoin \202 ammatory diseases: an update of clinical and genetic aspects. Rheumatology 2008; 47: 946 \200\22351. HAEMOCHROMATOSIS 506 Haemochromatosis Cardiac Cardiac involvement is uncommon, but an arrhythmia may be an early feature. Haemochromatosis is an inherited condition of iron stor- age, which results in a characteri stic arthropathy, \201 rst described in 1964. Liver Cirrhosis is a late feature. Epidemiology \200 Haemochromatosis is most common in Northern European populations \200\223 the highest prev alence being Ireland, UK, Brittany and Scandinavia. The annual incidence is 2 \200\2234/100 000 with a prevalence of 20 \200\22380/100 000. In the USA 1 in 227 white Caucasians are h omozygous for the HFE C282Y mutation. In Ireland the rate is 1 in 83. Males and females are affected equally. Males present typically between ages 25 \200\22370 and females after the men- opause. There is an association with HLA-A3-B14 (relative risk 23). Endocrine Diabetes is late manifestation and occurs when cirrhosis is established. Hypogona dism is also a late feature. Cutaneous Skin pigmentation is not diagnostic and is a slate gray color, rather than brown. It is caused by melanin and not iron. General investigations \200 Investigation is directed at establishing the diagnosis and assessing the extent and severi ty of organ involvement. Initial screening for the diagnosis is measurement of serum iron, transferrin, and ferritin. A transferrin satura- tion of >62% makes haemochromatosis very l ikely. Serum ferritin alone may be misleading as it is elevated in in \202 ammatory states . A liver biopsy is only needed for prognostic purposes in patients with severe iron overlo ad (ferritin >1000 g/l) and abnormal liver function. The acute phase response is normal a nd the rheumatoid factor negative. Etiology \200 Iron is poorly excreted in man and in haemochromatosis there is increased absorption from t he diet leading to iron overload. Hepcidin controls extracellular iron concentration by bin ding to and inducing the degradation of the cellular iron exporter ferroportin. Iron absorp tion is related to hepcidin, which has a key position in the pathological changes in haemoc hromatosis. De \201 ciency of hepcidin is seen in many iron overload states with increased iron absorption. The precise mechanism by which the HFE C282Y protein, ferroportin and hep cidin interact is unclear. Genetic screening HFE genotyping should be performed when screening iron studies are abnorm al. Homozygosity for the C282Y muta- tion or for the compound heterozygous C282Y/H63D con \201 rms the diagnosis. Genetics Haemochromatosis is an autosomal recessive condition, due to mutation in the HFE g ene located on the short arm of chromosome 6p21.3. The most common mutation is C282Y re \202 ecting mutation of cys to tyr at locus 282. A number of other mutations have been desc ribed, e.g. H63D (his to asp at locus 63). In Northern Europe 90% patients are homozygous f or C282Y and 5% heterozygous C282Y/ H63D. The compound heterozygotes are less severely af- fected. However, 25% of C282Y homozygotes do not de- velop iron overload. Imaging \200 There are typical changes of OA with joint space nar- rowing, subchondral sclerosis, and cy sts. Prominent hook-like osteophytes are present especially at the MCP joints. The pattern of joint involvement is not typical for OA, with involvement of the MCP, midcarpal, radioca rpal, elbows and glenohumeral joints. The 2nd and 3rd MCPs are typically involved. 30% of p atients have radiological evidence of chondro- calcinosis. Clinical features Key features on history \200 Onset of iron overload is uncommon before 30 years of age. Presentation is with gradual sti ffness, pain on use and enlargement of the MCP joints. There is evolution into a polyarticu lar arthropathy. There may be episodes of acute pseudogout, which may involve the knee, wri st, intervertebral disk and symphy- sis pubis. Fatigue is a common feature. Non-speci \201 c abdominal pain and discomfort may be the presentation of liver disease. Differential diagnosis \200 This is from other types of osteoarthritis and in \202 amma- tory arthritis. Secondary iro n overload is excluded by an absence of a history of blood transfusions, parenteral iron ad ministra- tion and anemia (b-thalassaemia, sideroblastic anemia). Porphyria cutanea tarda m ay present with raised trans- ferrin saturation and ferritin concentration with abnor- mali ties of liver function. The skin is more fragile with blisters and the pigmentation is deep er. The diagnosis is made on the demonstration of the presence of uropor- phyrins. Alcoholi c liver disease may be associated with increased ferritin and transferrin saturation. \200 Key features on examination Arthropathy Patients develop a characteristic pattern of OA, wi th in- volvement of the 2nd and 3rd MCP joints. The tenderness is mild and the joint is not warm. There is an absence of soft tissue swelling. CHAPTER 18 Miscellaneous diseases 507 Prognosis \200 Treatment \200 The rate of progression of the arthropathy is extremely variable, but regular venesection d oes not improve the arthropathy. The damage to synovial membrane and cartilage is irreversi ble. The overall prognosis is excellent if venesection is started early in the disease. Pat ients with cirrhosis have 200-fold risk of hepatocellular carcinoma. Therapy is directed to removing excess iron by venesec- tion. Initially this is weekly unti l transferrin saturation is normal with a ferritin 20 \200\22350 g/l. Maintenance phlebot- omy is thereafter required to maintain normal transfer- rin saturation. Venesection does no t appear to have a signi \201 cant impact on progression of the arthropathy. Treatment is other- wise symptomatic with analgesics, NSAIDs, and exercises. Liver function improves wit h venesection, as does the cardiomyopathy. Pathology Synovial biopsies characteristically show haemosiderin deposition in type B synov ial lining cells. Resources Patient organization The haemochromatosis society UK. www.haemochromatosis.org.uk Synovial \202 uid Synovial \202 uid is mildly in \202 ammatory and calcium pyrophos- p hate crystals may be present. Patient advice \200 Other OMIM: www.ncbi.nlm.nih.gov/entrez/ OMIM 235200 Family members should be screened as early initiation of regular phlebotomy can prevent dev elopment of systemic disease. Alcohol and excess vitamin C should be avoided as this can in crease iron absorption. ICD-10 E83.1 Disorders of iron metabolism References Adams PC, Barton JC. Haemochromatosis. Lancet 2007; 370: 1855 \200\22360. Bacon BR, Olynk JK, Brunt EM et al. HFE genotype in patients with haemochromatosis and othe r liver disease. Ann Intern Med 1999; 130: 953 \200\22362. Puechal X. Genetic haemochromatosis: why is discovery of the HLA-H gene of such interest to rheumatologists. Rev Rhumatisme 1997; 64: 527 \200\2239. [in English.] Schumacher HR. Haemochromatosis and arthritis. Arthritis Rheum 1994; 7: 41 \200\22350. See also Osteoarthritis Calcium pyrophosphate deposition disease Figure 18.2 Haemochromatosis, showing osteoarthritis MCPs joints. HAEMOGLOBINOPATHIES 508 Haemoglobinopathies Dactylitis \200 Haemoglobinopathies result from inherited defects in the structure and function of hemoglob in. Sickle cell disease is the most common haemoglobinopathy causing an arthropathy. In children aged 6 months to 2 years vaso-occlusive crisis occur in bones of hand and feet leading to dactylitis. Symptoms improve over 1 week but may recur. Epidemiology \200 Osteonecrosis \200 Sickle cell disease occurs in people from Africa, Southern Italy, Northern Greece, Southern Turkey, Saudi Arabia, and Central and Southern India. Painful crisis are more common men t han women. In men they occur most frequently between ages 15 and 25 years, in women the fre quency is constant between ages 15 and 40 years. Occurs in up to 20% of patients at the femoral head. Initially may be indistinguishable fro m an acute crisis, but the pain does not settle after 2 weeks. Pain gets worse on walking a nd at night. Osteonecrosis can occur at other joints particularly the shoulder, where there is pain and loss of range of move- ment. Osteomyelitis \200 Etiology Sickle cell hemoglobin (HbS) occurs when there is a sin- gle nucleotide substituti on in the B-globin gene, at position B6, valine is substituted for glutamic acid. The B-glo bin gene is located at 11p15.5. In hypoxic conditions HbS forms liquid crystals that deform the erythrocytes into rigid sickle shaped cells. This leads to vaso-occlusion. This also o ccurs in the other sickle syndromes. Usually follows an episode of painful crisis and should be considered if the crisis lasts m ore than 2 weeks. Multiple sites may be involved, which can be symmetrical. Septic arthritis \200 Uncommon in sickle cell disease, occurs in the presence of acute osteomyelitis, but more of ten as a result of hae- matogenous spread. Acute increase in pain in patients with known os teonecrosis of the hip should be assessed for septic arthritis. Genetics Sickle cell disease is an autosomal recessive condition, due to inheritance of the HbS gene from both parents (i.e. homozygous). The heterozygous state sickle cell trait is not associated with rheumatic disease. Other sickle cell syn- dromes occur when HbS is comb ined with other abnormal Hb genes, e.g. sickle cell HbC disease (HbS from one par- ent and HbC from the other), or HbS with B-thalassaemia (S- B+-thalassaemia.) Key features on examination Painful crisis \200 \200 There may be marked localized joint swelling. Patients develop jaundice. Dactylitis \200 \200 Clinical features Key features on history Painful crisis \200 Acute painful non-pitting swelling of hands and feet. Shortening of digits due to necrosis of the epiphysis is a consequence of previous dactylitis. Osteonecrosis \200 \200 A history of sickle cell disease is usually available but should be sort in a patient prese nting with painful veno- occlusive disease, dactylitis, or osteonecrosis from an appropriat e ethnic background. Painful crisis is the typical feature of sickle cell disease. One or m ore joints may become in \202 amed. The may spread either in an additive manner or be migr atory. Pain occurs most frequently in the juxta-articular regions of long bones, but also o ccurs the back, ribs, and rarely the abdomen. Acute back pain may be the only feature. Dura tion of the crisis is from a few minutes to several weeks, but persistence beyond 2 weeks i s unusual in uncomplicated crisis. Osteonecrosis is a late feature. Pain and marked loss of range of movement, especially at t he hip and shoulder.