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. Osteomyelitis and septic arthritis \200 Soft tissue swelling and persistent pyrexia. General investigations \200 Initial screening for the diagnosis is a sickle cell test, which should be performed in une xplained bone pain or osteonecrosis. If positive it should be followed with hae- moglobin e lectrophoresis. In each painful crisis hemoglobin and reticulocyte count should be determin ed to exclude an aplastic crisis. A raised ESR and leucocytosis suggest infection. In uncom plicated SS, the ESR is normal, but rises during the resolving phase of the crisis and to a much higher level in infection. The CRP is a more sensitive measure of the in \202 ammato ry response. Hyperuricaemia is common (40%), but acute gout is rare. Blood cultures and joi nt aspiration should be performed when sepsis is suspected. Sickle cell patients are partic u- larly prone to infections with Haemophilus in \202 uenzae, Streptococcus pneumoniae and Salmonella. There are four distinct phases to the crisis: \200 \200 \200 \200 Prodromal: the patient is restless and vaguely unwell. Initial: jaundice and increasing pai n. Established: pain reaches it maximum. Resolution: pain gradually decreases and resolves over 2 weeks. Precipitating factors include: \200 \200 \200 \200 Cold Pregnancy Emotional stress High altitude traveling CHAPTER 18 Miscellaneous diseases 509 Imaging Plain radiographs \200 Plain radiographs are not useful in the early stages of osteomyelitis. Osteonecrosis can be assessed using the Steinberg clas- si \201 cation system, but early in the process the X- ray is normal and MRI is more useful. MRI \200 MRI shows abnormalities due to osteonecrosis much earlier than X-ray and should be used. Th e overall sensi- tivity is reported to be 91%. Gadolinium-enhanced MRI demonstrates osteomy elitis with irregular marrow enhancement. Acute infarcts appear as thin linear enhancement. Ultrasound A \201 nding of >4 mm of subperiosteal \202 uid is suggestive of osteomyelit is. Differential diagnosis \200 Infection of bone or joint should always be considered. Rarely a chronic destructive synovi tis occurs, which needs to be differentiated from rheumatoid disease. Rheumatic fever is co mmon in the same regions as sickle cell disease and the migratory arthritis of rheumatic fe ver must be differentiated. The ANA is often positive, but SLE occurs no more frequently in these patient. Figure 18.3 Avascular necrosis of the hip in a patient with sickle cell disease. Pathology \200 Osteonecrosis of the femoral head should be treated with rest and avoidance of weight beari ng. Decompression should be considered in early osteonecrosis. The occlusion of small blood vessels in the bone marrow leads to many of the complication o f sickle disease, such as painful crisis, dactylitis, and osteonecrosis. Polymerization of HbS in a deoxygenated state leads to increased rigidity of red cells and vaso occlusion. Th is leads to hypoxia and tissue damage. Salmonella infection especially osteomyelitis is com mon in sickle cell disease. The reason is unclear, but may relate to reticuloendothelial fa ilure, iron overload, and defects in the alternate complement pathway. Resources Patient organizations Sickle Cell Association of America. Available at: www. sick lecelldisease.org Others OMIM: www.ncbi.nlm.nih.gov/entrez/ OMIM 603903 (sickle cell disease) Synovial \202 uid Synovial \202 uid is non-in \202 ammatory, straw colored and sterile in uncomplicated arthritis. ICD-10 coding D57 Sickle cell disease References Cordner S,De Ceular K. Musculoskeletal manifestations of haemo- Patient advice \200 Family members should be screened for the presence of abnormal haemoglobins. Advice about a voidance of sickle crisis. globinopathies. Curr Opin Rheumatol 2003; See also Osteoarthritis Calcium pyrophosphate deposition disease Osteonecrosis Osteomyeliti s Septic arthritis Treatment \200 Appropriate analgesia including is necessary. In severe crisis opiates may be needed. Rehyd ration is essential and may be intravenous. Intravenous antibiotics should be started if in fection is suspected. \200 hemophilia 510 Hemophilia De \201 nition De \201 ciency of factor VIII (Hemophilia A) or factor IX (Hemophilia B or Christmas disease) is due to X-linked inherited defects in the blood coagulation cascade r esult- ing in recurrent musculoskeletal hemorrhage. Milder bleeding episodes are less dramatic, and may be restricted to the subsynovium or be unrecognized by the patient. Muscle hemorrhage is acutely painful and may be crip- pling. Subacute arthropathy Follows recurrent hemorrhage into one or more joints, there is pain wi thout evidence of acute hemorrhage. Epidemiology \200 Factor VIII de \201 ciency has an incidence of 1:5000 male births and Factor IX de \201 c iency an incidence of 1:30 000 male births. There are no ethnic or geographical variations, and no HLA associations. Key features on examination Acute haemarthrosis \200 \200 The joint is swollen, hot, and very tender. Bruising appears as the swelling subsides. Etiology \200 Subacute arthropathy \200 Hemophilia is inherited as a sex-linked recessive trait. Thus, males only are affected and females are carriers. The factor VIII gene is located on the long arm of the X chromosome a t Xq28. It is 168kb long and has 26 exons. Factor VIII is a plasma glycoprotein which circu - lates in a non-covalent association with von Willebrand factor. A variety of mutations ha ve been described, the most common of which is a translocation in intron 22 which causes 40 \200\22350% of cases. The factor IX gene is located on the long arm of the X chromosome at Xq27. It is 34kb long and has eight exons. Missense and nonsense mutations account for 80% of mutations. There is no common mutation. De \201 ciencies of other clotting factors are very rare, as is the acquired form of factor VIII de \201 ciency. The severity of the ble eding disorder depends on the levels of plasma coagulation factors that, in turn, re \202 ect the precise mutation. Iron deposition appears to be important in the develop- ment of s ynovitis. Ferritin-induced production of super- oxide anions and OH radicals causes damage to both cartilage and synovium, which leads to \201 brosis of the joint. Examination reveals a \200\230boggy synovitis \200\231, with synovial thickening and chron ic effusion. Peri-articular muscles are weak and the joint ligaments lax. Chronic arthropathy \200 The affected joint is disorganized. There is bony thicken- ing, deformity, loss of range of movement, and crepitus. Joint contractures are present due to \201 brosis or ankylosis. Soft tissue swelling and effusions are uncommon at this stage. \200 Hemophiliac pseudotumour Destructive lesion occurring in bones associated with frac- ture, local infection and ulceration. Due to recurrent hemorrhage into the subperiosteal region, which then becomes encapsulated and subsequently enlarges. General investigations \200 Coagulation screen including bleeding time, platelet count, prothrombin time, partial throm boplastin time, factor VIII and factor XI levels will con \201 rm the diagnosis. The acute phase response is normal. RF and ANA are negative. The joint should be aspirated and the s ynovial \202 uid cultured, if there is doubt about the diagnosis. Clinical features Key features on history General Try to establish the nature and severity of the bleeding disorder. Does the patient receive factor VIII injections and which hemophi lia center does the patient attend. Imaging X-rays Plain radiographic appearances depend on the stage of disease. Acute haemarthrosis The diagnosis of hemophilia is usually well established before the \201 rst musculoskeletal bleeding episode. \200 Early disease \200 \200 \200 Periarticular soft tissue swelling. Periarticular demineralization. Increased radiodensity of synovium. Age of onset depends on the severity of the bleeding disorder. Weight-bearing joints on the dominant side are most commonly affected and the child \200\231s ability to walk is affect ed. Knee, elbow, and ankle are the most commonly affected joints. Intra-articular bleeding can occur spontaneously in severe disease and after minor trauma in moderate disease. Intra -articular hemorrhage presents with initial joint stiffness followed by acute pain, warmth, and swelling. Rising intra-articular pressure eventual stops the bleeding. Intermediate \200 \200 \200 Growth arrest lines (Harris lines). Widening or premature fusion of the epiphysis. Widening of the femoral or humeral intercondylar notches. Squaring of the inferior border of the pa tella. Proximal radial head enlargement. Increased talotibial slant and \202 attening of talus. \200 \200 CHAPTER 18 Miscellaneous diseases 511 Treatment Management is best performed in specialist hemophilia center with an appropriate multi disciplinary team. Late \200 \200 \200 \200 \200 Irregularity of cartilage with narrowing. Central and marginal erosions. Subarticular scler osis, bone cysts, osteophyte formation. Joint disorganization. Bony ankylosis. Acute arthropathy \200 Immediate factor replacement is required and may already been started by the patient at hom e. Prompt treatment of haemarthrosis is essential, aspira- tion is only needed when the dia gnosis is unclear, the joint very distended or where infection needs to be excluded. The jo int should be iced, elevated, rested, and appropri- ate analgesics used. Graduated physioth erapy, local ultrasound, isometric exercises are required to mobilize the patient. Ultrasound \200 \200 Useful to demonstrate degree of synovial hypertrophy. Assess soft lesions, such as muscle h aematoma. MRI \200 Demonstrates blood in the joint cavity and subsyn- ovium. Detect changes in hyaline cartila ge before changes become apparent using plain radiography. Assess degree synovial hypertrop hy. Subacute arthropathy \200 The development of the characteristic boggy synovitis indicates potential destructive disea se. Acute rapid treatment of bleeding is required. The use of early prophylactic therapy wi th factor replacement before joint damage occurs successfully prevents devel- opment of sub acute arthropathy. Physiotherapy to maintain muscle strength and prevent contracture develo pment is necessary. Intra-articular or oral corticosteroids only produce a short-term bene \201 t. Synovial \202 uid The synovial \202 uid is characteristically bloody, the \201 rst sa m- ple being heavily blood stained. Differential diagnosis \200 Acute arthropathy is usually readily recognized in previ- ously diagnosed patients. The mai n differential diagnosis of the single hot joint is infection, which should be excluded by synovial \202 uid culture. Rarely musculoskeletal hemorrhage is the presenting event. The differential of haemarthrosis then includes trauma (intra-articular fracture), bleeding di sorder (platelet deficiency, anti-coagulant therapy, acquired factor VIII de \201 ciency), blood dyscrasia, villonodular syno- vitis, joint neoplasms Von Willebrand disease (de \201 ciency or dysfunction of the adhesive glycoprotein von Willebrand factor), although mo re common does not present with acute haemarthrosis. Chronic arthropathy May not be completely preventable even with modern treatment and prophy lactic regimen. Joint arthroplasty (elbow, knee) should be considered, but is technically d if \201 cult. Ankle arthroplasty is less successful and consid- eration is still given to arthrodesis. Resources Patient organizations Haemophila Society (UK): www.hemophilia.org.uk Pathology Hemophiliac synovitis is characterized by synovial hyper- trophy, monocyte in \201 ltration, deposition of haemosiderin in the synovium, and subsynovium, and new vessel formation. Others OMIM: www.ncbi.nlm.nih.gov/entrez/ OMIM: hemophilia A 306700 OMIM: hemophilia B 3069 00 Patient advice \200 ICD-10 coding D66 Hereditary factor VIII de \201 ciency D67 Hereditary factor IX de \201 ciency Genetic counseling. X-linked recessive condition, which runs true in families. 80% of mothe rs of an isolated patient are expected to be hemophilia carriers. Rare condition resulting in bleeding disorder and arthropathy. Avoidance of trauma both accidental and surgical. Avo idance aspirin and other drugs affecting platelet function. Avoidance of intramuscular inje ction. References Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet 2003; 361: \200 1801 \200\2239. Resnick D. Bleeding disorders. In: Resnick D. Diagnosis of Bone and Joint Disorders, 4th edn. Saunders, 2002; 2346 \200\22373. SARCOIDOSIS 512 Sarcoidosis Sarcoidosis is a multisystem granulomatous disease of unknown cause. Key features on history Musculoskeletal \200 Chronic oligo- or polyarticular arthropathy occurs late in the disease, and is associated w ith interstitial lung disease and other organ involvement. Dactylitis: diffuse swelling of a digit that may be tender. De \201 nition Sarcoidosis is a multisystem disease of unknown etiology characterized by t he formation of non-caseating granulo- mata in affected organs. Key features on examination Musculoskeletal \200 Epidemiology \200 In the USA the incidence is 10.9/100 000 in Caucasians and 35.5/100 000 in Afro-Americans. The incidence in Scandinavia is 15 \200\22320/100 000. Females are affected more frequently . Onset is typically aged <40 years. There is seasonal clustering of acute sarcoidosis in t he spring. Oligo or poly articular involvement knees, ankles, wrists, and small joints of the hands an d feet. Joint destruction is rare. Dactylitis with soft tissue swelling over digits, and te n- derness and stiffness of neighboring joints is common. \200 \200 Muscle disease \200 Asymptomatic skeletal muscle involvement is common and a random muscle biopsy may con \201 rm the diagnosis. Acute sarcoid myopathy is rare and indistinguishable from acute polymyos itis, with development of acute proximal myopathy, raised CK, and myopathic changes on EMG. Chronic sarcoid myopathy presents with bilateral sym- metrical proximal muscle wasting and weakness. The CK is usually normal. Etiology \200 The etiology is unknown. However, three factors seem to be important. Exposure to a trigger ing antigen, acquired cellular immunity to the antigen, and develop- ment of effector cells that promote a non-specific in \202 ammatory response. In \202 ammatory alveolitis prece des granuloma formation and is composed of CD4+ T-cells and mononuclear phagocytes. Accumul ation and activation antigen-speci \201 c Th1 lymphocytes is critical to granuloma formati on. The mechanisms of granuloma resolution are not well under- stood. Acute sarcoidosis in is associated with HLA B8, DR3. HLA-DR3. No consistent non-HLA associations have been estab lished. Osseous sarcoidosis Bone lesions occur in up to 5% of patients, usually in those with chron ic cutaneous or internal organ involvement. Pulmonary Pulmonary \201 brosis is present in 25%. Cutaneous \200 Clinical features Acute sarcoidosis occurs typically as L fgren \200\231s syndrome: a tria d of constitutional illness, polyarthritis and erythema nodosum Skin involvement is common (25 \200\22335%). Macules, papules, and plaques may arise as sin gle or isolated lesions. Lupus pernio: violaceous lesions on nose, cheeks, lips and ears. Key features on history Systemic Fever and malaise are common. General investigations Investigation is directed at establishing the diagnosis, and assessi ng the extent and severity of organ involvement. \200 \200 \200 FBC: anemia of chronic disease. Acute phase response (ESR and CRP). Liver function: ALP may be raised in one-third of patients. Bone biochemistry: activated in macrophages in the gra nulomata increase hydroxylation of 25-hydroxyvita- min D to 3 to 1,25 hydroxyvitamin D3 and this leads to hypercalcaemia in 10% and hypercalcuria in 40%. Plasma 1,25 hydroxyvitamin D 3 levels are raised. ACE: angiotensin-converting enzyme (ACE) is produced by epithelioid ce lls of the granulomata and activated alveolar macrophages. Elevated ACE levels are seen in 40 \200\22390% of cases. Elevated ACE levels are seen in other granulomatous diseases and i n some non-granulomatous diseases such as Gaucher \200\231s disease, thyrotoxicosis, liver cirrhosis and diabetes mellitus. Musculoskeletal Typically begins in the ankles and may spread to knees, wrists, elbows, PIP s, and MCPs. Occurs in 70%. Monarthri- tis is uncommon. The axial skeleton and sacroiliac j oints are spared. Cutaneous Erythema nodosum occurs in up to two-thirds of patients with acute sarcoidosis. Key features on examination Musculoskeletal The ankle joints are typically warm, red, and v ery tender. Cutaneous Raised warm tender nodules (erythema nodosum) are typically present over the calv es, but may occur on the forearms. Radiological investigations \200 Chronic sarcoidosis This is uncommon and most cases occur in Afro-Carribean patients. Chest X-ray: this is abnormal in 95% of cases. In acute disease this may show bilateral hil ar lymphadenopathy. There may evidence of interstitial lung disease, which will need assess ment with high resolution CT. CHAPTER 18 Miscellaneous diseases 513 The arthritis lasts from 2 weeks to 4 months. In a Spanish series 8% had active disease at 2 years and 6% relapsed (Mana et al., 1999). Overall, 60% of cases remit spontaneously with 10-20% responding to corticosteroids. In 10 \200\22330% there is a chronic course, of thes e 50% have progressive pulmo- nary disease. Osseous sarcoidosis cysts, lytic lesions with periosteal reaction, reticular lace-like chan ges, sclerosis, and destructive changes. Nuclear medicine \200 Gallium-67 citrate scintigraphy reveals increased uptake by sarcoid granulomata typically i n the parotid and lach- rymal glands (Panda sign). Uptake is non-speci \201 c and occurs i n lymphoma, TB, and fungal infection. 18F-FDG-PET may be useful in assessing extent organ i nvolvement and identifying potential biopsy sites. Pathology The sarcoid granuloma is well circumscribed; round or oval, non-caseating, and ma de up of compact radially ar- ranged epithelioid cells. The giant cells are Langerhans type . The center of the granuloma is composed of CD4+ Th1 T cells and macrophage derived cells. Bronchoscopy and bronchiolar alveolar lavage \200 The lavaged \202 uid typically shows a 30 \200\22350% lymphocyto- sis with a CD4/CD8 T-ce ll ratio >3.5. Pulmonary function testing. This shows restrictive pat- tern with reduction in vital capacity, residual volume, and total lung capacity. 65% of patients have air \202 ow limitation at presentation. Patient advice \200 Acute disease: self-limiting process most likely to be a reaction to infection and typicall y no treatment is required. Chronic disease: life-long condition requiring treat- ment with corticosteroids. Biopsy of an affected organ should be obtained where possible to con \201 rm diagnosis and , in particular, to exclude infection or malignant disease. Kveim test: the reagent is no l onger available. Treatment \200 Acute sarcoid arthritis: most patients respond well to NSAIDs. Occasional patients with sev ere arthropathy require a short course of corticosteroids (prednisolone 15 \200\22340 mg/da y). Chronic sarcoid arthritis: many patients simply require NSAIDs. Those with major organ involvement need cor- ticosteroids. Cutaneous sarcoidosis may respond to hydroxychloro- qui nt. Low dose once weekly oral methotrexate may permit reduction in prednisolone dosage. The role of other immunosuppressive agents and TNF- alpha blockade is unknown, although positi ve isolated case reports support their use. Differential diagnosis \200 This is from other types of acute in \202 ammatory arthritis, including reactive arthritis , rheumatoid disease, and occasionally gout. Chronic sarcoid arthritis may resemble RA, but is gener- ally milder. Monarticular disease must be differentiated from infection. Upper a irways disease needs to be distinguished from Wegener \200\231s granulomatosis, keratoconju nctivitis, and parotid involvement from Sj gren \200\231s syndrome. The uvei- tis needs to be distinguished from spondyloarthropathy and Beh et \200\231s syndrome Erythema nodosum has many causes. Other granuloma- tous diseases, such as Mycobacterial infection, fungal in fection, berylliosis, and local reactions to tumors or lymphoma. Appropriate serological in vestigations, biop- sies and cultures may be required in regions where Mycobacterial/fungal diseases are common. Resources Patient organizations American lung association: www.lungusa.org Foundation for s arcoidosis research: www.stopsarcoid- osis.org Disease assessment \200 ICD-10 coding D86 Sarcoidosis Severity of involvement of target organs should be care- fully assessed Slit lamp examinati on is required to assess asymptomatic eye involvement. References ManaJ, Gomez-Vaquero C, Montero A et al. L fgren \200\231s syndrome revisited: a study of 186 patients. Am J Med 1999; 107: 240-5. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med Prognosis \200 2007;357:2153-65. Acute sarcoidosis (including L fgren \200\231s syndrome) has an excellent prognosis with a 90% remission rate. PANNICULITIS 514 Panniculitis Aetiopathogenesis of EN \200 Panniculitis is in \202 ammation of adipose tissue most typically within subcutaneous fat. Erythema nodosum (EN) is the most common variety. Up to 50% of cases of EN have an underlying cause, with sarcoidosis and infection being the most common. L fgren \200\231s syndrome is a triad of EN, acute arthropathy, and bilatera l hilar lymphadenopathy. Classi \201 cation Panniculitis can be divided into four categories based on the histopath ological appearance. Table 18.4 Causes of erythema nodosum Table 18.3 Classi \201 cation of the panniculitides Systemic Sarcoidosis Septal panniculitis Erythema nodosum Pregnancy In \202 ammatory bowel disease Vilanova \200\231s disease Connective tissue diseases Lobular panniculitis Weber-Christian disease Malignancy Rothmann \200\223Makai syndrome Sweet \200\231s syndrome Subcutaneous fat necrosis of the newborn Beh et \200\231s disease Post-steroid Infections Streptococcal pharyngitis Calcifying Mycobacterial Enzymatic Coccidioidomycosis Pancreatic Blastomycosis Alpha1-antitrypsin de \201 ciency Histoplasmosis Physical or factitious Psittacosis Histiocytic cytophagic syndromes Yersinosis Lipodystrophy syndromes Salmonellosis Connective tissue associated Cat scratch fever Lipodermalosclerosis Leprosy Mixed panniculitis Lupus profundus Drugs Antibiotics \200\223 penicillin, sulphonamides Beh et \200\231s erythema nodosum Oral contraceptive pill Panniculitis/vasculitis Leucocytoclastic vasculitis Polyarteritis nodosa Weber \200\223Christian disease Key features on history Fever \200 \200 \200 Erythema induratum From Callen (2004) Recurrent tender nodules that can occur anywhere. Arthralgias, myalgias. Abdominal pain due to mesenteric panniculitis. Epidemiology \200 The panniculitides can occur at any age, but most typi- cally in young adults. They occur m ore commonly in women. EN has an annual incidence of 2 \200\2233/100 000; other types of pa nniculitis are much rarer. EN is associated with HLA-B8. Key features on examination Recurrent multiple subcutaneous nodules, these result in fat de struction and scar formation. \200 Investigation Biopsy reveals lobular panniculitis with fat degeneration, foamy histiocytes, and giant cell formation. Erythema nodosum Key features on history EN is usually acute and self-limited, and heals wi thout scar formation. \200 Pancreatic panniculitis Patients with a wide variety of pancreatic conditions may develop a lobular panniculitis. Acute development of one or more tender red nodules on the anterior shins. Prodromal fever, malaise, arthralgias. Key features on examination \200 Subcutaneous fat necrosis. \200 There may be an accomp anying polyarthritis with osseous intramedullary fat necrosis. Key features on examination \200 \200 Tender red palpable nodules over the anterior shins. Older lesions appear bruised, ulcerati on is rare. Lupus profundus Key features on history \200 Panniculitis is a rare complication of SLE occurring in 1 \200\2233% of patients with SLE. Activity of panniculitis appears not to mirror activity of SLE. CHAPTER 18 Miscellaneous diseases 515 Key features on examination \200 The lesions are tender red-blue subcutaneous nodules, which may ulcerate. Typically they oc cur on face, upper arms thighs, and buttocks. Alpha-1 antitrypsin de \201 ciency Alpha-1 antitrypsin is associated with panniculitis. Hi sto- logically, the appearances are a lobular, septal, or a mixed panniculitis. Post-steroid panniculitis Panniculitis may follow steroid therapy especially in chil- dren. It may recur with reuse of corticosteroids. The pathogenesis is not known. Histiocytic cytophagic panniculitis This is a chronic histiocytic disease of subcutaneous f at, ac- companied with panniculitis, fever, serositis, and lymph a denopathy. The haemophag ocytic syndrome may occur. Prednisolone and immunosuppression may be useful. Lipoatrophic panniculitis Rothmann \200\223Makai syndrome (lipogranulomatosis subcuta- nea) is a form of subcutaneous lipoatrophy that occurs after an in \202 ammatory disease in ch ildren. There are multi- ple erythematous lesions on the extremities which heal with subcut aneous atrophy. Fever may be present. Treat- ment is uncertain. Figure 18.4 MRI Sagittal T1-weighted showing multiple low signal areas indicating osteonecr osis and marrow oedema. In a patients with metastatic pancreatic fat necrosis. Differential diagnosis The differential diagnosis of EN includes other forms of panniculiti s, insect bites (history and evidence of a puncture wound), thrombophlebitis, and celluliti s. Investigation Histologically, there is evidence of both septal and lobular panniculitis. Treatment \200 EN is usually self-limiting, NSAIDs may be needed for arthralgias/myalgias. Chronic relapsi ng forms of panniculitis may respond to corticosteroids or other immunosuppressive drugs. General investigations \200 Infection screen, especially looking for evidence of upper respiratory tract infection, thr oat swab, and ASO titre. Chest radiograph looking for infection (especially Mycobacterial) or bilateral hilar lymphadenopathy sug- gestive of acute sarcoidosis. Appropriate serologic al investigations, biopsy, and cul- tures may be required in areas where Mycobacterial and fungal infections are common. Investigation for in \202 ammatory bowel disease is unneces- sary in asymptomatic patients, as this usually sympto- matic when accompanied by panniculi tis. Autoantibody serology if there is evidence of a connec- tive tissue disorder Amylase a nd lipase should be measured in patients pos- sibly with pancreatic disease. Biopsy if the diagnosis is in doubt. A deep wedge biopsy including subcutaneous fat is necessary References Callen JP. Panniculitis. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC (eds) Oxford Textbook of Rheumatology, 3rd edn. Oxford: 2004: 1031 \200\22335. See also Sarcoidosis SLE ALKAPTONURIA 516 Alkaptonuria De \201 nition A rare autosomal recessive condition resulting from lack of homogentisic ac id oxidase, and the accumulation of homo- gentisic acid causing ochronosis and ochronotic a rthropa- thy. Ochronosis is the characteristic black pigmentation seen in alkpatonuric pati ents. Pigmentation of the auricular cartilage appears as a slate- blue or gray color in the conch a, antihelix, and tragus. General investigations \200 The acute phase response is normal. RF and ANA are negative. HLA-B27 is generally negative. A sample of urine should be left to stand. It will darken if it contains excessive amounts of homogentisic acid. Homogentisic acid levels in plasma and urine may be determined by hi gh-performance liquid chromatography. Alkaptonuria was the \201 rst human condition in which the pattern of Mendelian inheritan ce was recognized by Gar- rod in 1902. Garrod in 1908 hypothesized that a speci \201 c enz yme was lacking. Imaging X-rays On plain radiography of the lumbar spine the characteristic \201 ndings ar e: \200 \200 \200 Epidemiology \200 \200 The highest frequency occurs in Slovakia (1/19 000). The overall frequency is 1/250 000 \200\223 1/million live births. Wafer like calci \201 cation of intervertebral disks. Narrowing of disc spaces. Ossi \201 cation of the of the ligaments. Etiology \200 Alkaptonuria is due to lack of the enzyme homogentisic acid oxidase (HGO). The gene for thi s enzyme is located on 3q21 \200\22323. A variety of different mutations have been describe d including nonsense, missense and frame shift mutations. There does not appear to be any c orrelation between the HGO mutation and severity of disease. Homogentisic acid oxidase cata lyzes the oxidative cleav- age of the ring of homogentisic acid into maleylacetoace- tic ac id. Homogentisic acid then accumulates slowly in the tissues, resulting in the charactersti c black pigmenta- tion. The renal clearance of homogentisic acid is high suggesting active renal tubular excretion. Inheritance as an autosomal recessive condition. The exact mechani sm by which pigment deposition results in arthropathy is not known. In peripheral joints the appearances of osteoarthritis de- velop about 10 years after the s pinal changes. Multiple intra-articular radio-opaque loose bodies may be seen in the knees. Synovial \202 uid Effusions occur in around 50% of patients. The synovial \202 uid is c haracteristically non-in \202 ammatory, containing mainly mononuclear cells (100 \200\2237 00 cells/mm3). Pyrophos- phate and apatite crystals have been found in alkaptonuric patient s. \200 Clinical features Key features on history \200 In infancy, the \201 rst feature may be the mother noticing a dark discolouration of the nappies. In adults there is often a history of dark urine (in half of patients this is the presenting feature) or urine that dark- ens on standing. Musculoskeletal \200 Joint pain often starts before the age of 30 years. Initially, this is spinal and then a pe ripheral arthritis develops. Episodic joint in \202 ammation occurs later. Cutaneous \200 Pigmentation of the sclera and ear is rarely seen before 20 \200\22330 years of age. Adult alkpatonuric patients may have dark urine or urine that darkens on standing. Key features on examination Musculoskeletal \200 \200 Figure 18.5 Lumbar disc calci \201 cation in a patient with longstanding ochronosis. Marked spinal stiffness at all levels with kyphosis. Large joint osteoarthritis is common, particularly knee, hip, and shoulder. Small joint involvement is unusual. They may be a joi nt effusion. Differential diagnosis \200 \200 The main differential diagnosis is from osteoarthritis, ankylosing spondylitis, and calcium pyrophosphate depo- sition disease. Ankylosing spondylitis can be distinguished from ochro - nosis by the presence of syndesmophytes, erosion, and fusion of the sacroiliac joints. Cutaneous \200 Ochronotic pigmentation in the eye is visible at the insertion of the rectus muscles, and m ay spread to the conjunctiva and sclerae. CHAPTER 18 Miscellaneous diseases 517 Resources Patient organizations The Alkaptonuria society. www.alkaptonuria.info Osteophytosis on X-ray is not present in ochronosis, but is a typical feature of osteoarthr itis. Ochronosis affects shoulders and sacroiliac joint, which are less frequently involved in osteoarthritis. Others OMIM: www.ncbi.nlm.nih.gov/entrez/ OMIM 203500 Pathology Biopsies show ochronotic pigment in the cartilage. This is located within collage n bundles causing loss of striation, swelling, and fracture. ICD-10 coding E70.2 Disorders of tyrosine metabolism