and CRP are often only moderately raised. Clinical features and their management Skin and mucosa involvement (see Table 18.1) \200 Oral aphthous ulcers are always present, and may precede other features by several years. Idiopathic oral aphthous ulcers are common, and by themselves do not imply the presence of Beh et \200\231s. The ulcers associated with Beh et \200 \231s are indistinguishable from ordinary ulcers, but tend to be multiple, more frequent, a nd may heal with scarring. Genital ulceration in men is most prominent over the scrotum (90%). Urethritis is not seen unless there is a meatal ulcer. In women, the labia are commonly affected. Cervical ulcers are rare. Skin lesions may be nodular (resembling erythema nodosum), acneiform, or vasculitic. The pathergy reaction, a hyperreactivity of the skin to a needle prick, is peculiar to this syndrome and pyoderma gangrenosum. After skin puncture with a needle, a papule or pustule forms in 24 \200\22348 h. The reaction is seldom found in patients from Northern Europe or the United States, but is positive in 60% and 70% of patients from Japan and Turkey, respec tively. Mild oral and genital ulceration may respond to oral colchicine 0.6 mg po bid. More severe disease may require AZA 2.5 mg/kg/day. Nonsteroidal anti-in \202 ammatory drugs can help c ontrol pain. Eye disease \200 This is a serious complication and a negative prognostic factor. Eye dis ease is more common in men and patients <25 years of age. \200 Disease is bilateral in 90 % of cases and is usually a chronic relapsing panuveitis. The presence of a hypopyon (cells in the anterior chamber) BEH \207ET \200\231S DISEASE 501 Table 18.1 The clinical \201 ndings in Beh et \200\231s disease Lesion Prevalence (%) Aphthous ulcers 97 \200\223100 Genital ulcers 80 \200\22390 Skin lesions 80 Eye lesions 50 Arthritis 40 \200\22350 Thrombophlebitis 25 Neurological disease 1 \200\22315 Gastrointestinal disease 0 \200\22325 is almost always associated with severe retinal vasculitis, after which there is almost alw ays some structural damage despite treatment. The extent of this damage determines the cour se of eye disease in Beh et \200\231s syndrome. Topical steroids and mydriatics with close supervision may be suf \201 cient in mild disease, but severe disease requires the addition of AZA 2.5 mg/kg/day or anti-TNF- A therapy to the topical regimen. Musculoskeletal system involvement \200 Joint involvement is seen in about 50% of patient s. \200 It is usually mono- or oligoarticular, but can be symmetric, mimicking RA. Chronic synovitis is rare, nonerosive, and nondeforming. \200 In general, knees, ankles, wrists, and elbows are involved (in descending order of frequency). Back pain is rare. \200 Pain may respond to NSAIDs. In \202 ammatory disease often requi res the introduction of methotrexate 20 \200\22325 mg PO/SQ weekly. Cardiovascular and pulmonary involvement \200 Endocarditis, myocarditis, pericarditis, co ronary vasculitis, and ventricular aneurysms can all occur but are rare. Venous involvement is one of the main features of Beh et \200\231s syndrome. Thrombophlebitis occurs in 25% of all patients. Limb venous thrombosis is often o bserved. Occlusion of the suprahepatic veins \200\224Budd \200\223Chiari syndrome \200\224c arries a high mortality. Pulmonary embolism is rare despite high rates of thrombophlebitis. It might be explained by the difference in architecture of thromboses seen in Beh et \200\231s syndrome versus normal (e.g., postoperative) thromboses. The former tends to adhe re throughout its length to the vein wall; the latter tends to have a long, nonadherent and potentially embolic tail. Arterial lesions can occur anywhere. Aneurysms may develop and rupture. This is frequently fatal. CHAPTER 18 Miscellaneous conditions 502 The pulmonary pathology of Beh et \200\231s disease is related to arterial vasculitis. A neurysms, thromboses, and infarcts may be found. \200 Aspirin and NSAIDs can be used to r elieve the symptoms of phlebitis. Aneurysms and arterial occlusion require cytotoxic therap y with cyclophosphamide 2.5 mg/kg/day and prednisone 1 mg/kg/day; surgery may also be indic ated. There remains debate about whether to use heparin or oral anticoagulants for the thro mbophlebitis, although most physicians will choose to treat with anticoagulation in additio n to immunosuppression. Neurological involvement \200 Prospective surveys suggest a prevalence rate of 5% for neu rological disease in the condition. Pyramidal signs are the most common, followed by cerebellar and sensory symptoms and signs. The most common site is the brainstem. Meningeal irritation and dementia may also occur. As is the case with eye disease, central nervous involvement is o ften more severe in men. In contrast to other vasculitides, peripheral neuropathy is unusual. \200 CNS disease sho uld be treated with IV methylprednisolone, and cyclophosphamide should be considered. Gastrointestinal involvement \200 While seen in up to one-third of patients in Japan, gas trointestinal disease is rare in patients from the Mediterranean basin. The basic pathology is mucosal ulceration, seen most often in the ileum and cecum. The course is one of relapse and remission, with a distinct tendency to pe rforate. Ulceration may respond to prednisone 0.5 \200\2231 mg/kg/day, sulfasalazine 2 \200\2233 g/d ay, or in \202 iximab. Surgical evaluation may be necessary to manage severe sequelae. Renal involvement \200 This is seen much less than might be expected in a systemic vascul itis. There are occasional reports of glomerulonephritis. Amyloidosis usually presents with nephrotic syndrome. About 5% of men develop epididymitis. Treatment focuses on symptom control. Treatment of Beh et \200\231s disease \200 Colchicine 0.6 mg po bid should be used to treat orogenital ulceration; dapsone (25 \200\223100 mg PO daily), thalidomide, and anti-TN F- A therapy all have demonstrated ef \201 cacy. Azathioprine 2.5 mg/kg/day should be considered for the treatment of the systemic manifesta tions of Beh et \200\231s. Methotrexate 20 \200\22325 mg/week may also be effective, par ticularly for articular symptoms. Arteritis and other life-threatening manifestations shoul d be treated with cyclophosphamide 2.5 mg/kg/day. In \202 iximab (e.g., 5 mg/kg IV every 4 weeks) or rituximab (e.g., 375 mg/m 2 IV weekly for 4 weeks) may be effective for treating ocular manifestations of Be h et \200\231s that do not respond to topical therapy. \200 Warfarin should be used in the usual way for thrombotic episodes. If thrombosis occurs in the setting of disease \202 are, immunosuppression may be required as well. This page intentionally left blank CHAPTER 18 Miscellaneous conditions 504 Sarcoidosis \200 Sarcoidosis is a multisystem disease of unknown etiology, characterized by the presence of multiple, noncaseating granulomas in involved tissue. It occurs worldwide, but the prevalence, clinical features, and outcome varies. It is seen more often in developed versus underdeveloped, Western versus Eastern, and in Northern vers us Southern European countries. Sweden and Denmark have prevalence rates of 60 per 100,000: the United Kingdom 20 per 100,000. In the United States, sarcoidosis is 10 \200\22315 time s more prevalent in the African American population than in Caucasians; African Americans m ay also present with a more severe form of this disease. There is also an increased inciden ce of sarcoidosis in families. Recent studies have suggested a link between HLA B8, DR3, an d acute sarcoidosis with arthritis. Acute sarcoidosis presents with rapid onset fever, erythema nodosum, and hilar lymphadenopa thy. This condition has a high rate of remission and a good prognosis; the chest radiograph clears within 1 year in 60% of cases. Chronic sarcoidosis is less common and has a subtle, insidious, progressive, and highly var iable clinical course (see Table 18.2). \200 Sarcoidosis is rare in childhood, and usuall y indolent. If arthritis occurs, it is usually before 5 years of age and associated with eye and cutaneous disease. Musculoskeletal manifestations of sarcoid Joints \200 Distinctive patterns of arthropathy are seen in both acute and chronic sarcoidosis. In acute disease, transient arthralgias ma y precede the emergence of other symptoms. Sarcoid arthritis is usually symmetric and persi sts for 1 \200\2234 months on average, and occurs in association with erythema nodosum (EN) . Effusions are common at the knees and ankles. After recovery, acute sarcoidosis only occa sionally recurs. \200 Chronic arthritis is uncommon in sarcoidosis; when it does occur, i t usually appears in the form of monoarthritis or involvement of the spine. Again, knees an d ankles appear to be most often involved with in \202 ammatory disease, characterized by acute exacerbation with synovial thickening and effusions. Unlike acute sarcoidosis, a hist ory of EN is unusual. Chronic polyarthritis is also more frequent in women than men. It may cause joint deformity and destruction. Bones \200 Bone involvement occurs in 5% of all patients with sarcoidosis. Bone cysts are seen most often in the hands and feet and are most frequently seen in patien ts with persistent disease and/or lupus pernio (i.e., erythematous induration of the skin a cross the face). Cysts are often asymptomatic and found by chance on plain radiographs. Cli nically they can present in the \201 ngers and toes with \200\234sausage-like \200\235 s wollen digits. SARCOIDOSIS 505 Table 18.2 Clinical manifestations in chronic sarcoidosis Organ/system Clinical features Lung Parenchymal disease in > 90% of cases Skin Lupus pernio, plaques, and nodules Ocular Uveitis, conjunctivitis, sicca Lymphatics Lymphadenopathy, splenomegaly Bone marrow In \201 ltration Hepatic Failure, granuloma, portal hypertension Renal Nephrocalcinosis, granuloma, glomerular disease Cardiac Arteritis, cardiomyopathy, conduction abnormalities Nervous system Central and peripheral neuropathy. intracerebral lesions. Meningitis. Seizures Granulomata Endocrine and reproductive organs. Gastrointestinal tract. Salivary/lacrimal glands. Nose, tonsils, and larynx Other radiological features include thickening of cortical bone, acrosclerosis, and joint destruction. Occasionally lytic lesions appear in vertebral bodies, leading to back pain and crush fract ures. Lytic lesions may also be seen in the skull bones and long bones. Muscles \200 Often asymptomatic, in the early stages of acute sarcoidosis granulomatous muscle involvement is common (50 \200\22380%). It may present as proximal pai n, tenderness, and weakness. Involvement may be focal with a granulomatous mass or diffuse and symmetrical myopathy, the latter leading to progressive weakness and atrophy. Electromyography looks similar to that of polymyositis. Diagnosis and treatment of sarcoidosis \200 A patient with a new diagnosis of sarcoidosis should receive an electrocardiogram, pulmonary function tests, computed tomography of the chest, and slit-lam p examination, in addition to a thorough physical examination and symptom-driven evaluation . The red blood cell count is usually normal. Leukopenia can be seen in up to one-third of cases, and eosinophilia in one-fourth. Thrombocytopenia is a rel atively common problem. The ESR may be elevated in the acute phase, particularly if EN is present. Reports of hypercalcemia vary widely from 2 \200\22360%. The level tends to \202 uctuate and the reasons for such wide variation remain unclear. Liver function tests may be abnormal. \200 One-third of patients have signi \201 cant pr oteinuria. CHAPTER 18 Miscellaneous conditions 506 Epithelial cells found in the granuloma produce angiotensin-converting enzyme (ACE). Serial measurements of this enzyme may be useful in monitoring the course of the disease, althoug h it is not a reliable screening test for establishing the diagnosis. As sarcoidosis can resemble other diseases such as lymphoma and tuberculosis, the diagnosis should be con \201 rmed by histology. Peripheral tissues s uch as skin or salivary glands may be helpful. Transbronchial lung biopsy is widely used an d highly sensitive and speci \201 c. Acute, transient disease may resolve spontaneously, and require only supportive care. More severe disease may require treatment with corticosteroids, either alone or in combination with methotrexate. Addition of hydroxychloroquine may also help the skin and joint manifestations of sarcoid. In \202 iximab may be useful to treat refractory forms of this disease, including lupus pernio. Most patients with chronic disease will require steroid therapy, but the decision to treat is more often related to systemic involvement than to articular disease. No therapy is required for asymptomatic osseous, cystic bone disease, or asymptomatic muscl e disease. The place for steroids in chronic sarcoid myopathy remains uncertain. This page intentionally left blank CHAPTER 18 Miscellaneous conditions 508 Miscellaneous skin conditions associated with arthritis Panniculitis Panniculitis refers to in \202 ammation within the subcutaneous fat. It is a dynamic in \202 ammatory process i nvolving neutrophils, leukocytes, and his- tiocytes that causes \201 brosis, and, sometim es, granulomatous change. There are four categories of panniculitis, based on histopatholog y: Septal panniculitis \200 Lobular panniculitis \200 Mixed type septal and lobular \200 Panniculitis with vasculitis. Septal panniculitis This includes erythema nodosum (EN) and Vilanova disease (subacute nodular migratory panniculitis). EN is a common, acute, and self -limiting condition found typically over the anterior tibial surface. It usually heals with in 4 \200\2236 weeks without scarring, though a rare form can cause ulcera- tion and a migr atory form can occur for several years (more often in women around 45 years old). The cause s and associations of EN are shown in Table 18.3. Lobular panniculitis Listed below are a number of conditions that cause lobular panniculiti s. \200 Weber \200\223Christian disease : a relapsing, febrile, nodular nonsuppurative sy ndrome. There may be multiple recurrent nodules plus fever; arthralgias, myalgias, and abdo minal pain are common. Any area of the body containing fat can become involved, e.g., mesen tery, heart, lung, liver, kidney. There is a 10 \200\22315% mortality. Investigations may s how: \200 typical histological features on biopsy \200 elevated ESR \200 anemia \200 leukopenia or leukocytosis Many clinicians believe that Weber-Christian disease does not exist as an independent entit y, and that this one term has been mistakenly used to represent several diseases with simil ar presentations. Therefore, at minimum, it should be considered a diagnosis of exclusion; prior to mak- ing this diagnosis, it is important to rule out other causes of panniculitis, including: \200 Lipogranulomatosis : this group of conditions tends to occur in children . Multiple lesions, often on the extremities, resolve with subcutaneous atrophy. Poststeroid use : the pathogenesis of this rare condition is not understood. It seems to be limited to children, occurs on withdrawal of corticosteroids, an d may clear up on steroid readministration. A 1 -antitrypsin de \201 ciency : may respond to doxycycline. \200 Acute pancreatitis . MISCELLANEOUS SKIN CONDITIONS ASSOCIATED WITH ARTHRITIS 509 Table 18.3 Etiological causes of EN Cause Examples Infection Streptococcal TB/leprosy Yersinia/Salmonella Histoplasmosis Blastomycosis Psittacosis Drugs Penicillin Sulfonamides Pregnancy Diseases Sarcoidosis In \202 ammatory bowel disease Collagen vascular disease (SLE, scleroderma, dermatomyositis) Malignancy (rare) Sweet \200\231s syndrome Calcifying panniculitis is a feature of chronic renal failure. It is not the same as metastatic calci \201 cation. The prognosis is poor even with good calcium-phospha te balance. Parathyroidectomy may help. \200 Lipodermatosclerosis : this condition may be a result of venous insuf \201 ciency and thrombophlebitis. It should be treated with comp ression stockings. Intralesional corticosteroids or low-dose aspirin may also help. Lupus profundus is a rare manifestation of chronic cutaneous SLE, occurring in <3% of cases of SLE. The lesions are usually tender and may ulcerate and calci fy. The lesions commonly occur on the face, upper arms, and buttocks, and may underlie an a rea of discoid lupus. The lesions do not seem to follow the course of the systemic disease. It may respond to steroids. Factitious : self-in \202 icted injuries may mimic the appearance of a panniculitis. Panniculitis with vasculitis This is seen in small-vessel and medium-vessel vasculitis. The reader is referred to Chapter 14. Treatments include: \200 Treatment of the underlying d isease or agent \200 NSAIDs \200 Bed rest and limb elevation \200 Antimalarials \200 Steroids CHAPTER 18 Miscellaneous conditions 510 Dapsone \200 Colchicine \200 Azathioprine \200 Cyclosporine. Neutrophilic dermatoses The neutrophilic dermatoses are a group of noninfectious disorders char- acterized by the presence of an angiocentric, primary neutrophilic in \202 am- mator y cell in \201 ltrate. The disorders can be divided into those that cause vessel wall dest ruction (vasculitis) and those that do not. Table 18.4 lists the causes of noninfectious ne utrophilic dermatoses. The majority of dis- eases are discussed in detail in their own chap ters in this book. This sec- tion will discuss Sweet \200\231s syndrome, and pyoderma gangr enosum. Sweet \200\231s syndrome \200 This condition is rare and occurs more often in women than men (ratio 3.7:1), between the ages of 30 and 70 years. It has occasionally been reported in ch ildren. The pathogenesis is unknown. The characteristic features are myalgias, fever, arthralgias, and painful erythematous plaq ues (or occasionally nodules resembling erythema nodosum). Untreated, the lesions resolve o ver 6 \200\2238 weeks but new lesions will continue to appear. The condition is usually an acute, steroid-responsive, self-limiting disorder. If longer-term treatment is required, st eroid dosage may be reduced by the addition of an NSAID, dapsone, colchicine, or possibly m ethotrexate. A secondary cause for the condition should be sought (see Table 18.5). Pyoderma gangrenosum \200 This is an uncommon, ulcerative, cutaneous condition associated with several systemic diseases (see Table 18.6). The lesion is characterized by an erythematous, violaceous border overhanging a central area of ulceration and necrosis. The lesions start as discrete pustul es, most often on the legs, and are often extremely painful, healing with scars. There is no speci \201 c treatment. An underlying disease should be sought. Treatments include topical sodium cromoglycate or 5-amino salicylic acid, oral sulf onamides, dapsone, and corticosteroids. \200 It is important to exclude potential mimics. Chronic infections, hypercoagulable states (such as the antiphospholipid antibody syndrome ) and some forms of vasculitis can all lead to lesions that resemble pyoderma gangrenosum. Multicentric reticulohistiocytosis \200 This is a rare systemic disease, primarily a diso rder of adults in their \201 fth decade. It is recognized clinically by the combination o f papular and nodular skin lesions and a severe destructive polyarthritis. \200 The disor der is distinct from the solitary nodule lesion of the reticulocytoma in that the latter is not associated with systemic disease. Multicentric ret iculohistiocytosis may involve any organ system. MISCELLANEOUS SKIN CONDITIONS ASSOCIATED WITH ARTHRITIS 511 Table 18.4 Noninfectious neutrophilic dermatoses Group Examples Nonangiocentric Psoriasis Reactive arthritis Acne fulminans Angiocentric and vessel destruction Leukocytoclastic vasculitis Polyarteritis nodosa Angiocentric, no vessel destruction Sweet \200\231s syndrome Pyoderma gangrenosum Bowel-associated dermatosis \200\223arthritis Beh et \200\231s disease Rheumatoid arthritis Ulcerative colitis Familial Mediterranean fever Table 18.5 The associations with Sweet \200\231s syndrome Associations Examples Hematological malignancy Leukemia Lymphoma Myelodysplastic disorders Solid tumors Breast Gastric Genitourinary Colon Infectious diseases HIV Hepatitis Tuberculosis Salmonella In \202 ammatory bowel disease Ulcerative colitis Crohn \200\231s disease Rheumatic diseases Rheumatoid arthritis Systemic lupus erythematosus Sj gren \200\231s syndrome Beh et \200\231s disease CHAPTER 18 Miscellaneous conditions 512 Table 18.6 Diseases associated with pyoderma gangrenosum Association Examples Rheumatic diseases Seronegative spondyloarthropathy Rheumatoid arthritis Osteoarthritis Psoriatic arthritis Systemic lupus erythematosus Granulomatosis with polyangiitis (Wegener \200\231s) Sarcoidosis Takayasu \200\231s arteritis Hematological diseases Leukemia Myelo \201 brosis Gammaglobulinemia Polycythemia vera Gastrointestinal diseases In \202 ammatory bowel disease Chronic active hepatitis Primary biliary cirrhosis Other Solid tumors Diabetes mellitus C7 complement de \201 ciency The arthritis may mimic a RA pattern. Often the distal interphalangeal joints are involved and the destruction may give a picture similar to arthritis mutilans. The skin lesions occur in approximately 90% of cases. Histologically, the in \201 ltrate c onsists of multicentric giant cells and histiocytes from the monocyte-macrophage lineage. T he lesions are usually numerous, nonpruritic, skin colored (or yellow/brown), and range in size from millimeters to several centimeters in diameter. They occur most often on the dors um of the hands and on the face (at the nose, corner of the mouth, and ears). Extensive fac ial involvement may lead to a \200\234leonine \200\235 facies. About 25% of cases have xanthelasma. \200 One-third of cases have constitutional symptoms /signs such as weight loss or fever. Approximately 25% of cases have been reported to have malignant (mostly solid tumor) diseas e. The investigation of the condition, therefore, requires a thorough screen for rheumatic and malignant disease. There are no speci \201 c laboratory markers. Histology is helpful. Biopsies may be taken from skin or in \202 amed synovium. MISCELLANEOUS SKIN CONDITIONS ASSOCIATED WITH ARTHRITIS 513 The differential diagnosis includes: \200 rheumatoid or psoriatic arthritis \200 sarcoi d dactylitis \200 xanthoma \200 histiocytosis X \200\224a disorder of children \200 h istiocytoma or tendon sheath giant-cell tumor \200\224usually solitary. \200 As a rule, t he condition waxes and wanes, and spontaneous remissions can occur. Multicentric reticulohistiocytosis has been associated with numerous forms of malignancy, a nd a new diagnosis should prompt a thorough investigation. Patients with multicentric reticulohistiocytosis may quickly develop a disabling arthritis, and should be treated aggressively. For patients with mild disease, methotrexate may be su f \201 cient, but some patients may require treatment with cyclophosphamide to prevent pro gressive damage. CHAPTER 18 Miscellaneous conditions 514 Chronic regional pain syndrome This syndrome is characterized by variable dysfunction of th e musculoskel- etal, skin, neurological, and vascular systems. It may occur in a variety of situations with a number of clinical manifestations varying around central core features. As such, several terms have evolved, describing the same phenomenon: \200 Re \202 ex sym pathetic dystrophy \200 Sudeck \200\231s atrophy \200 Shoulder \200\223hand syndrome \200 Transient osteoporosis \200 Regional migratory osteoporosis \200 Posttrauma painf ul osteoporosis Complex regional pain syndrome (CRPS) has two types; type 1 is symp- toms i n the absence of nerve injury, and type 2 ( \200\234causalgia \200\235) is symptoms in the presence of nerve injury. Epidemiology \200 CRPS is a common disorder. It affects both sexes equally and occurs at any age in all races and geographical regions. Typically the syndrome involves the dista l part of a limb, e.g. forearm or foot. The early clinical features of the condition include: pain \200 soft tissue swelling (may be synovitis if over a joint) \200 reticular/livedo rash \200 warmth over affected part occasionally there may be localized \200 sweating and piloerection. The pain has several particular characteristics and is often described as burning. The features include: \200 allodynia \200\224an otherwise innocuous stimulus pro duces pain \200 hyperalgesia \200\224increased pain perception to a given stimulus \200 hyperpathia \200\224delayed overreaction, often after repetitive cutaneous stimulus. The net effect is abnormal tenderness to even minor stimuli. \200 Trauma (whether acciden t, burn, surgery, etc.) is the most common triggering event. The event may have even seemed trivial or minor at the time. Several neurological conditions may act as triggers, including, for example, hemiplegia and meningitis. Peripheral nerve root injury may also lead to the syndr ome. Pregnancy, tumors, and prolonged immobilization have also been linked as possible triggering factors. However, 25% of cases have no clear trigger. It is important to try and identify psychosocial stresses. \200 The signs and symptoms of pain, swelling, etc. (see above), are traditionally placed as stage I of the condition. In most cases the symptoms persist and \202 uctuate, though they may just gradually resolve . Stage II is a period of dystrophic change. This tends to occur several months after onset of the disorder. The affected region becomes CHRONIC REGIONAL PAIN SYNDROME 515 cool, pale, and often cyanosed in color with abnormal sensation (dysesthesia). There is a d ecrease in hair and nail growth, osteopenia develops, and eventually atrophy (stage III) of skin and subcutaneous tissue occurs; at this point the condition becomes dif \201 cult to treat and reverse. Most cases tend not to progress beyond stage I or, at most, early stage II. Investigations \200 Laboratory values, including acute phase reactants and metabolic pro \201 les, are normal. However, there may be evidence of bone demineralization, with elevat ed 24-hour urine hydroxyproline excretion. Although essentially a clinical diagnosis, CRPS does have some radiological and nuclear medicine imaging characteristics. No technique is diagnostic. Plai n radiographs, DEXA, and MR may show features of osteoporosis. Thermography can demonstrate changes in cutaneous temperature. \200 Perhaps of most value , and high speci \201 city, is the triple-phase technetium scintigraphy study, showing three phases of abnormal early regional blood \202 ow, blood pool, and late bone uptake respectively. Management \200 Success in treatment of this condition probably hinges on focusing on the whole individual and not the regional symptoms, and making an early and accurate diagnosis . Attention to anxiety, psychosocial stressors, pain behavior, and sleep disturbance is imp ortant. The patient often requires repeated reassurance and counseling. The aim should be t o resume premorbid levels of activity if possible. In this respect, early intervention with physical therapy and hydrotherapy should be considered. Tricyclic antidepressants can help correct sleep disturbance and increase the pain threshold. TENS may help pain control and allow entry into a physical activity program. In severe cases, regional sympathetic or ganglion blocks can control pain suf \201 ciently to start more vigorous physical therapy or exercise programs. Some clinicians have also had success with corticosteroids and with pamidronate. There are no controlled trials of this or any other therapy mentioned above. CHAPTER 18 Miscellaneous conditions 516 Relapsing polychondritis \200 This is an uncommon multisystem disorder of unknown etiolog y, characterized by episodic and sometimes progressive in \202 ammation of cartilage leading to destruction and \201 brosis. Common sites of involvement include the ear, nose, larynx, joints, heart, and eyes (cornea and sclera) (see Table 18.7). Similar patterns of disease may be seen in granulomatosis with polyangiitis (Wegener \200 \231s); also, some patients with relapsing polychondritis are ANCA+. The disease predominantly affects Caucasians in the fourth to \201 fth decades of life. Approximately 30% of cases have an underlying systemic rheumatic or autoimmune disease such as RA, systemic lupus, Sj gren \200\231s syndrome, thyroiditis, or ulcerative colitis. Patients exposed to levamisole-contaminated cocaine are sometimes mistakenly diagnosed with relapsing polychondriitis, due to the appearence of purpuric lesi ons on the outer ear. Levamisole, however, is not associated with auricular in \202 ammati on. There are no speci \201 c laboratory tests. The diagnosis is made on clinical grounds. Treatment of relapsing polychondritis \200 There are no controlled trials and the conditi on is rare. Intervention is based on anecdotal experience. Mild symptoms may be controlled with NSAIDs alone. Dapsone may also be of value. Corticoste roids (high doses, 1 mg/kg daily) may control systemic disease, particularly respiratory co mplications. Persistent or severe cases may be treated with azathioprine, methotrexate, or cyclophosphamide. Patients should be assessed for tracheal involvement (e.g., stridor or evidence of extra-th oracic obstruction on pulmonary function tests). Some cases may require temporary or perman ent tracheostomy if laryngeal involvement is severe. RELAPSING POLYCHONDRITIS 517 Table 18.7 Extent of organ involvement in relapsing polychondritis Organ Clinical feature Prevalence (%) External ear 95 Arthritis Nondeforming and nonerosive 85 Nose 48 Eye Episcleritis, uveitis, retinal vasculitis 57 Respiratory tract Dysphonia, dyspnea, stridor 67 Internal ear 53 Skin Erythema nodosum vasculitis, Beh et- like ulceration 38 Kidney Glomerulonephritis (poor prognosis) 8 Heart Pericarditis, aortic valve incompetence, heart block 8 Blood vessels Aneurysms 12 Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med 1998; 129: 114 \200\223122. CHAPTER 18 Miscellaneous conditions 518 Miscellaneous disorders of synovium Pigmented villonodular synovitis (PVNS) \200 The term PVNS is used for a group of conditions that are characterized by the proliferation of synovial cells and supporting tissues of the joint, t endons, and bursa. The condition is rare (estimated 2 cases per million). \200 As the name implies, there is a villous and nodular proliferation. This is nonmalignant and associated with iron and fat deposition. Repeated small hemorrhages and lipid deposits stain the synovium red-brown and yellow, respectively. The cause of the condition remains unknown though some studies have proposed a link with chronic repetitive trauma or hemarthroses. Experimental models and clinical experience with patients with bleeding disorders have not, however, reproduced the condition. \200 The classic presenta tion is with a monoarthritis. Any age may be affected though it tends to occur more often in both sexes in the third or fourth decade. T he knee is the most commonly affected joint and \200\234diffuse \200\235 disease is more a ggressive and more likely to recur. \200 Insidious onset of pain and swelling in the abse nce of trauma, with a serosanguinous synovial \202 uid aspirate and a characteristic syno vial biopsy are the basis for a diagnosis of PVNS. There are some important conditions to c onsider in the differential diagnosis: \200 malignant synovioma \200 synovial hemangiom a \200 synovial chondromatosis \200 tuberculous arthritis \200 amyloidosis \200 hem ophilia. Imaging may be helpful. Plain radiographs are often normal, but it may show soft tissue swe lling that can be radiodense with hemosiderin deposition. Calci \201 cation, however, is n ot a feature of PVNS and would suggest a malignant lesion or perhaps chondromatosis (see be low). \200 Erosions and subchondral cysts (also on nonweight-bearing surfaces) can be see n. Loss of joint space can occur late in the condition. Typically, this is not associated w ith juxta-articular osteoporosis or osteophyte formation. MRI can be highly suggestive of P VNS if there is suf \201 cient hemosiderin and fat deposition in the lesion. Treatment of PVNS \200 Localized forms of PVNS are treated by marginal excision of the le sion. \200 The prognosis is good. \200 Diffuse forms of PVNS tend to be progressive and recurrent. Treatment techniques have included synovectomy, radiation therapy, arthrodesis, and arthrop lasty. No one technique has particularly good results; however, there is only limited exper ience and little long-term follow-up. The most commonly reported treatment is surgical synovectomy. MISCELLANEOUS DISORDERS OF SYNOVIUM 519 Synovial chondromatosis \200 This condition is characterized by chondrometaplasia of the subsynovial connective tissues. The joint is \201 lled with a thickened white/blue nodula r synovium. The cause is unknown, the disorder uncommon, and the process nonmalignant. It tends to occur more often in middle-aged men and has never been reported i n prepubertal childhood. Clinically the condition resembles PVNS (above) but tends to be slowly progressive and sometimes self-limiting with regression. Plain radiographs may show punctate calci \201 cation outlining the joint margin. The diagnosis should be con \201 rmed on synovial biopsy. In rare cases there may be transformation to a chondrosarcoma. Treatment is surgical and usually managed with arthroscopy, removing loose bodies and/or the synovial membrane. CHAPTER 18 Miscellaneous conditions 520 Amyloidosis \200 A number of disorders and clinical settings are associated with the extracellular deposition of amyloid, a proteinaceous, \201 brillar material. The low solu bility of amyloid and its relative resistance to proteolytic enzymes contributes to the irr eversible and often progressive course of amyloidosis. Despite morphological similarities (including the formation of a beta pleated sheet), amylo id is a heterogeneous group of proteins. All types of amyloid \201 brils have a carbohydr ate moiety in the form of glycosaminoglycans and proteoglycans. Most forms of amyloid also contain the extra \201 brillar protein, amyloid-P (protein AP). The different amyloid proteins are often related to distinct clinical forms of amyloidosis. At present, at least 17 proteins have been characterized. The detail of these proteins is beyond the scope of this book. However, two types are important as manifestations of a resp onse to chronic systemic in \202 ammation; amyloid-L (AL) and amyloid-A (AA). Protein AL consists of monoclonal immunoglobulin light chains and is seen in idiopathic and myeloma-associated amyloidosis. The clinical features of AL and A A are shown in Table 18.8. Protein AA (derived from serum amyloid A (SSA), an acute phase apolipoprotein), is associat ed with conditions such as secondary reactive amyloidosis and FMF (see Table 18.9). The mechanisms by which the various precursor proteins are converted to insoluble amyloid \201 brils, the reasons for the predilection of certain pr oteins for particular organs and tissues, and the reasons why not all cases of a particular chronic in \202 ammatory disorder develop amyloid are not clear. The most studied mechani sms are those associated with the reactive AA type amyloidosis. Clinically, amyloidosis may be associated with nephrotic syndrome, cardiomyopathy, hepatomegaly, peripheral neuropathy, malabsorption, and orthostatic hypoten sion. Reactive AA amyloidosis is mainly associated with long-standing infectious or noninfectious in \202 ammation, and less frequently with cancer. In the context of rheumatic disorders AA amyloidosis is mainly seen in: \200 Adult RA \200 JIA \200 AS There are several rheumatic conditions that are rarely associated with AA amyloidosis. In t hese conditions there is a relatively low level of the acute-phase protein SAA. These condi tions include: \200 SLE \200 systemic sclerosis \200 Sj gren \200\231s syndrome AMYLOIDOSIS 521 Table 18.8 The clinical features of AL and AA amyloidosis Organ/condition Comment AL amyloidosis Heart Death occurs in 50% of cases from: restrictive cardiomyopathy, congestive heart failure, co nduction disturbances Lungs 90% develop cough and dyspnea Skin 40% of cases: papules, nodules, tumors Neuropathy 10% of cases get carpal tunnel syndrome Macroglossia Vasculopathy Amyloid arthropathy Autonomic disturbance Common to AL and AA Weakness Fatigue Weight loss Renal Nephrotic syndrome/renal failure \200\224major cause of death in AA*, cause of death in one -third of AL patients Gastrointestinal tract Malabsorption, obstruction, diarrhea, hepatosplenomegaly* In AA amyloid the spleen, liver, and kidneys are often involved \201 rst. CHAPTER 18 Miscellaneous conditions 522 Diagnostic procedures \200 The diagnosis of amyloidosis is made by tissue biopsy (usually abdominal subcutaneous fat), and alkaline Congo red stain showing the amyloid deposits as a pple green/yellow under the polarizing microscope. The strong calcium-dependent af \201 nity of protein AP for amyloid \201 brils is also u sed diagnostically in radiolabeled serum amyloid protein (SAP) scintigraphy. This technique may localize amyloid and could be of value in assessing degrees of response to treatment. Other laboratory tests include DNA analysis to detect the genetic variants of proteins know n to make up the hereditary amyloidoses. Treatment of amyloidosis \200 The condition is progressive and there is no cure. Marked heterogeneity of the hereditary amyloidoses makes counseling dif \201 cult as well. The pr ocesses by which the disorder may be controlled include liver transplantation for lysosomal amyloidosis and bone marrow transplantation. For patients with AL amyloidosis, treatment with melphalan and prednisone prolongs survival. In the rheumatic diseases, cytotoxic drugs such as cyclophosphamide (often in combination with corticosteroids) have improved the prognosis in RA and JIA patie nts. Familial Mediterranean fever \200 This condition has been in the literature since the ear ly 1900s and was more recently characterized in the 1960s. Most cases (80%) present before the age of 20 and it is very rare to present with a \201 rst attack after the age of 40. Abnormalities of the gene coding for the protein pyrin (on chromosome 16) have been identi \201 ed and constitute the only test speci \201 c for the diagnosis of FMF. FMF is an autosomal recessive disorder. It most frequently affects peopl e of eastern Mediterranean descent, especially Armenians, Arabs, and Sephardic and Ashkenaz i Jews. The most common symptoms of abdominal pain and pleurisy are related to serositis, present i n up to 95% of cases. 75% of cases develop an arthritis that may be erosive and is most oft en isolated to a single joint. A rash with dermal neutrophil in \201 ltration (rather than a vasculitis) is common and looks not unlike erysipelas.