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Chapter 51 Miscellaneous Diseases and Complications

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 51 Miscellaneous Diseases and Complications

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Giovanna Cirigliano and Stefano Bombardieri

Amyloid arthropathy
Arthropathy in hemochromatosis
Rheumatic manifestations of hematologic disorders
Multicentric reticulohistiocytosis
Pigmented villonodular synovitis (PVNS)
Sarcoidosis
Storage diseases

I. Amyloid arthropathy

Amyloidosis is a disorder characterized by the extracellular deposition of an insoluble fibrous protein in the connective tissues or in one or more organs. Based on its staining with iodine and sulfuric acid, and on the mistaken belief that it was similar to cellulose, Virchow in 1854 designated this protein as amyloid.

During the past 25 years , the belief that a single amyloid substance appears during the course of several diseases has been refuted by a body of evidence showing that there are actually many types of amyloidosis. Each type is associated with a specific protein, and the resulting organ failure can be linked to the location, quantity, and ratio of deposition. The protein (P) itself consists of a homogeneous hyaline, eosinophilic material identifiable pathologically by three features: Congo red binding with a unique green-yellow birefringence under polarized light; a characteristic ultrastructure distinguished by fine, nonbranching, rigid fibrils 70 to 100 … in diameter; and the presence of the serum amyloid P component, which belongs, together with C-reactive protein, to a family of proteins termed pentraxins because of their characteristic structure (made up of paired pentagonal subunits ). Several different molecules have been associated with all forms of amyloid deposition ”the P component, apolipoprotein E, and heparan sulfate proteoglycan ”but the role of these molecules is still unclear.

The amyloidoses may be classified clinically as follows :

1. Primary amyloidosis and myeloma-associated amyloidosis, which show no evidence of predisposing disease and are characterized by the deposition of amyloid AL protein (immunoglobulin: k or l light chains).
2. Secondary or reactive amyloidosis, which is associated with chronic infectious or chronic inflammatory diseases and is characterized by the deposition of protein AA.
3. Heredofamilial amyloidosis.
4. Hemodialysis-associated amyloidosis.
5. Senile amyloidosis.
6. Localized amyloidosis.

The amyloidoses are of interest to rheumatologists because of their demonstrated association with long-standing inflammatory joint disease accompanied by amyloid deposition in the kidneys, liver, and spleen. However, the clinical presentation of arthropathy is rare; it has been seen in association with the deposition of AL protein, the amyloid associated with the immunoglobulin light chain; b ₂ -microglobulin in patients with chronic renal failure. Arthropathy is occasionally associated with transthyretin (TTR) amyloid (transthyretin is the precursor of amyloid protein).

1. Primary and myeloma-associated amyloidosis. These two forms of amyloidosis are characterized by the deposition of fibrils of AL amyloid made up of the monoclonal chain of immunoglobulin, the production of which indicates an underlying monoclonal plasma cell dyscrasia. Recent data also suggest the presence of structurally abnormal light chains.
   1. Clinical picture. Amyloid fibrils may localize in the synovial membrane and tendon sheaths, in the synovial fluid, and in the articular cartilage in a small percentage of patients with AL deposition. Clinical arthropathy in not common, although when seen it is chronic and may involve the small or large joints (shoulders, wrists, knees, or fingers) either symmetrically or asymmetrically . Stiffness (but not pain) is characteristic, together with swelling, limitation of motion, and subcutaneous nodules. Shoulder involvement may be particularly striking, with accumulation of amyloid at the joint producing the shoulder pad sign.
   2. Diagnosis. Radiography may show soft-tissue swelling and generalized osteoporosis with or without lytic lesions; joint space narrowing is not seen, and erosions are rare. The diagnosis can be confirmed by an examination of the synovial fluid and, when necessary, by synovial biopsy. The synovial fluid is noninflammatory and yellow or xanthochromic, and it may contain fibrils that have the tinctorial and ultrastructural features of amyloid. Clinicians must keep in mind the importance of the differential diagnosis with rheumatoid arthritis; a biopsy of the involved tissue may be needed. Careful evaluation for the presence of primary plasma cell dyscrasia and systemic organ involvement must also be carried out.
2. Hemodialysis- related amyloidosis. The second form of amyloid deposition associated with significant articular involvement is the deposition of b ₂ -microglobulin in patients with chronic renal failure undergoing long- term dialysis treatment. Use of the cellulose-based cuprophane dialysis membrane appears to be associated with a higher incidence of amyloidosis; the incidence is lower in patients undergoing peritoneal dialysis. Rarely does b ₂ -microglobulin amyloidosis develop in patients with renal failure before they begin dialysis.
   1. Clinical picture and diagnosis. b ₂ -Microglobulin amyloidosis involves the musculoskeletal system, with infiltration of the carpal ligaments, formation of bone cysts (frequently in apposition to the joints), scapulohumeral periarthritis, stiff and painful fingers, and destructive cervical spondyloarthropathy with cyst formation and occasional odontoid fracture. Cervical disease usually takes the form of vertebral end plate erosion without osteophyte formation. Rapid joint destruction then usually follows. Median nerve compression is very common with its attendant carpal tunnel syndrome.

      Ultrasonography of the wrist is useful to identify the characteristic thickening of the carpal ligaments. Sonograms of the shoulder can help to distinguish amyloidosis from other forms of shoulder disease.

      Radiographs will often show subchondral radiolucent bone cysts consisting of amyloid deposits and erosion. Systemic deposits are rare, and specimens obtained by abdominal fat pad aspiration (the simplest screening test) are usually negative for amyloid deposits. In patients with chronic renal failure, other conditions, such as secondary hyperparathyroidism, aluminum overload, and apatite crystal deposition, may occasionally play a contributory role in arthropathy, and such conditions should be identified.

   2. Therapy . In patients with either the primary or myeloma-associated form of the disorder, amyloidosis is treated directly, the goal being to reduce the number of cells producing the amyloid precursor, with a resultant reduction in the protein product and fibril formation.

      In hemodialysis-associated amyloidosis, renal transplantation can halt the disease progression but will not relieve the symptoms caused by already existing lesions. Pain cannot be relieved with surgery, but functional improvement may be obtained in joints that are accessible by arthroscopy. Proper monitoring of both the dialysis procedure and the patient's phosphate-calcium metabolism can help decrease the risk for destructive arthropathy.

II. Arthropathy in hemochromatosis. Hemochromatosis is one of the most common genetic disorders characterized by excessive body stores of iron and by the deposition of hemosiderin, both of which can cause tissue damage and organ dysfunction. Approximately one in every 250 “300 persons is homozygous for this mutation. Idiopathic hemochromatosis is an autosomal recessive disorder associated with two-point mutations on the HFE gene located on the short arm of chromosome 6. It rarely appears before the age of 40 unless there is a family history, and men are affected 10 times more frequently than women, who are protected by physiologic blood losses.

Increased intestinal iron absorption and visceral deposition can lead to the classic features of hepatic cirrhosis, cardiomyopathy, diabetes mellitus ( bronze diabetes), pituitary dysfunction, sicca syndrome, and skin pigmentation. Liver abnormalities are probably the most constant manifestation. However, hemochromatosis is usually symptomless and is often detected only accidentally . Other presenting manifestations include constitutional symptoms such as weakness, lethargy, and increased sleep requirements.

Arthropathy is present in 40% to 60% of patients. It sometimes constitutes the first manifestation but more often occurs later, even following treatment. The expression of hemochromatosis with arthritis is most common in homozygotes, although the pathogenesis of the arthritis is unknown. Prolonged excessive iron ingestion , as practiced by the South African Bantu tribesmen or as the result of repeated blood transfusions for chronic hypoproliferative anemia and thalassemia, may also result in iron deposition. When not associated with tissue damage, this disorder is known as hemosiderosis; when organ damage is present, it is called secondary hemochromatosis.

1. Clinical picture. Chronic progressive arthritis, predominantly affecting the second and third metacarpophalangeal and proximal interphalangeal joints and resembling rheumatoid arthritis, is the presenting feature in about one-half of all cases. Hemochromatosis can also affect the larger joints, such as the shoulders, hips, knees, and ankles. A progressive destructive osteoarthritis may be seen. The arthropathy causes stiffness and pain in the hands, often after excessive use, and symmetric, mildly tender joint enlargement without erythema or increased warmth. Sometimes, acute episodes of inflammatory arthritis may occur secondary to calcium pyrophosphate deposition. This form of chondrocalcinosis occurs in 15% to 30% of patients and involves the cartilage of the knees, wrists, intervertebral disks, and symphysis pubis.

   Yersinia septic arthritis is an unusual complication that may arise because of the predilection of this microbe for an iron-rich environment.

2. Diagnosis. The erythrocyte sedimentation rate is normal and rheumatoid factor is absent. The synovial fluid shows good viscosity , with leukocyte counts below 1,000/mm ³ . During acute episodes of pseudogout, synovial fluid leukocytosis and calcium pyrophosphate crystals may be found. Radiographs show cystic lesions with sclerotic walls, joint space narrowing, sclerosis, osteophytes, and osteoporosis. These radiologic changes may mimic those of osteoarthritis. Hemochromatosis should be suspected in the presence of raised serum iron and ferritin concentrations and increased saturation of transferrin, a plasma iron-binding protein. An effective screening algorithm includes a fasting morning transferrin saturation. If the percentage is > 50% and a serum ferritin is high, HFE testing is appropriate. Needle biopsy of the liver will confirm the diagnosis. Synovial biopsy in hemochromatosis will show iron deposition in the type B cell linings of the synovium.
3. Therapy. The arthritic symptoms may be brought under control by nonsteroidal antiinflammatory drugs (NSAIDs), although sometimes arthroplasty is required. Excess iron can be removed from the body by weekly phlebotomy. Phlebotomy usually does not relieve the arthropathy, however, and the damage to the synovial membrane and cartilage seems to be irreversible.

III. Rheumatic manifestations of hematologic disorders

1. Hemophilic arthropathy. Hemophilia is an inherited, X-linked recessive disorder of blood coagulation found almost exclusively in males. Female heterozygotes are asymptomatic carriers of the disease. Hemophilia A is caused by a factor VIII deficiency and hemophilia B (Christmas disease) is caused by a factor IX deficiency. Recurrent joint hemorrhages resulting in a synovial proliferative response and chronic inflammation are responsible for the arthropathy associated with hemophilia.

   Hemarthrosis, the most common bleeding manifestation, occurs in up to two- thirds of all patients affected by hemophilia. It may occur spontaneously or as the result of minor trauma, and the onset includes stiffness, pain, warmth, and swelling. The joints usually affected are the knees, elbows, and ankles.

   The pathogenesis of hemophilic arthropathy is not yet completely understood , but it may result from excessive iron deposition in the synovial tissue and articular cartilage. Because prothrombin and fibrinogen are absent, the blood in the joint remains liquid. The plasma is gradually resorbed and the remaining red cells undergo phagocytosis by the synovial lining cells and macrophages. Hemosiderin is found in synovial lining cells, where it may be toxic, causing chronic inflammation with proliferation of the synovium and pannus formation.

   1. Clinical features. Three stages of hemophilic arthropathy can be distinguished:
      1. Stage 1. Acute hemarthrosis is often the initiating event in hemophilic arthropathy, occurring when a child begins to walk. It is manifested by pain, warmth, swelling, and limitation of motion. The episodes can vary in severity from mild subsynovial hemorrhage to tense hemarthrosis. The age at onset and the frequency of these acute episodes depend on the severity of the factor deficiency.
      2. Stage 2. Subacute hemophilic arthropathy often follows repeated episodes of intraarticular hemorrhage. It manifests in the form of persistent synovitis with synovial thickening, chronic joint effusion, and varying degrees of pain. Polyarticular involvement is rare. Muscle weakness and joint laxity contribute to bleeding from the friable synovium, which causes chronic damage.
      3. Stage 3. Chronic hemophilic arthropathy is characterized by joint deformity, fibrous ankylosis, and osteophytic overgrowth. Soft-tissue swelling and joint effusion are less common in this stage, and the pain is fluctuating and variable. Late manifestations include muscle hemorrhage, muscle cysts, and osseous pseudotumors.
   2. Diagnosis. Hemophilia can be detected on the basis of laboratory tests measuring factor VIII and factor IX levels, which are directly correlated with the severity of the hemophilia and the ensuing hemarthrosis. The complete absence of either factor is associated with spontaneous bleeding in the muscles and joints; a level of 1% to 5% is associated with either spontaneous bleeding or bleeding after minor trauma; a level of 5% to 25% may be associated with excessive bleeding after minor surgery; and a level of 25% to 50% can result in excessive bleeding after major surgery or injuries. In patients with acute hemarthrosis, other diagnoses that must be considered include pigmented villonodular synovitis, the use of anticoagulant drugs, and joint trauma.

      Conventional radiology shows the typical findings of degenerative arthritis: joint space narrowing, subchondral sclerosis, and subchondral cysts. In children, radiographic findings include epiphyseal irregularities, squaring of the inferior patella, and enlargement of the proximal radius in the elbow . Ultrasound examination and magnetic resonance imaging (MRI) can provide detailed information regarding the degree and rate of progression of the articular disease.

   3. Treatment. Replacement therapy is essential to improve the longevity and prognosis of hemophiliac patients. Prompt, appropriate treatment for the hemarthrosis is vital and may include cold applications, analgesics, and joint immobilization followed by a carefully designed physiotherapy program. Aspiration (after factor replacement) is less commonly performed unless the joint is very tense or sepsis is suspected. Corticosteroids, whether oral or intraarticular, do not seem to be effective. Chronic arthropathy may be treated with NSAIDs. Joint replacement arthroplasty can be performed in those patients with advanced joint destruction. It demands a team approach with optimal factor replacement.
2. Sickle cell disease and b -thalassemia. In the hemoglobinopathies, osteoarticular symptoms may arise as a result of bone and joint involvement secondary to juxtaarticular-periarticular bone infarcts or synovial ischemia and infarction. Sickle cell crises can produce a painful arthritis of the large joints with effusion; the synovial fluid is typically noninflammatory. Local bone ischemia resulting from venous occlusion by sickle cells may cause osteonecrosis of the femoral head in up to one-third of patients; this osteonecrosis, when advanced, can be successfully treated with total arthroplasty. In about one-third of infants with sickle cell disease, dactylitis secondary to vascular occlusion in the bones of the hands and feet may represent the first manifestation of the disease. Children with sickle cell disease are prone to infection, and Salmonella osteomyelitis is seen with increased frequency in all stages of the disease.

   Thalassemia is associated with musculoskeletal complications. In b -thalassemia minor, recurrent asymmetric arthritis may be seen, whereas in b -thalassemia major, manifestations may include osteoporosis, pathologic fractures, and epiphyseal deformities. Treatment of the arthritis associated with sickle cell disease consists of supportive therapy, intravenous hydration, oxygen , folate supplementation, and analgesics.

3. Arthritis and monoclonal gammopathies. An association of the paraproteinemias and arthritis has been widely reported in the literature, in particular during the course of myeloma, Waldenstr m's macroglobulinemia, and primary amyloidosis. The presence of an erosive arthritis has also been described in patients affected by monoclonal gammopathies of uncertain significance. In these cases, arthritis may occur either as a rheumatoid-like symmetric polyarthritis or as an atypical oligoarthritis. The course is generally slow but progressive. The pathologic mechanism potentially responsible for the arthritic process is the deposition of paraprotein-derived material in the synovium with consequent activation of the inflammatory response. (See section I. above.)
4. Cryoglobulinemia. The cryoglobulins are immunoglobulins that reversibly precipitate at low temperatures . They are present in a variety of autoimmune, neoplastic, and infectious disorders and may be divided into two categories. The type 1 cryoglobulins are single monoclonal proteins, usually immunoglobulin G (IgG), sometimes IgM, and rarely IgA, that are generally associated with myeloma and macroglobulinemia.

   The type 2 cryoglobulins consist of a macromolecular complex of more than one class of immunoglobulin; hence, they are termed mixed cryoglobulins. One component of the mixed cryoglobulins is usually an IgM rheumatoid factor, which is responsible for the formation of the complex and for its precipitation properties. The mixed cryoglobulins have been further subdivided into those in which one component is monoclonal and those in which all the components are polyclonal.

   Mixed cryoglobulinemia is a systemic vasculitis characterized by the presence of cryoglobulins with rheumatoid factor activity. Although mixed cryoglobulinemia is a disease of multifactorial origin, the hepatitis C virus has been shown to play a central role in its pathogenesis. The disease is an immune complex-mediated disorder with a number of immunologic phenomena that are often triggered by hepatitis C.

   1. Clinical picture. The most common clinical manifestations of mixed cryoglobulinemia are arthralgias and purpura. Arthralgias are present in the majority of cases, usually recurring intermittently during the course of the disease. They most frequently involve the small and medium- sized joints such as the hands, knees, ankles, and elbows. Mild, transient, nonerosive arthritis is far less common. Other organs that may be involved in mixed cryoglobulinemia are the liver and kidneys.

      Liver involvement is present in more than two-thirds of patients with mixed cryoglobulinemia but is generally asymptomatic. It may precede the onset of mixed cryoglobulinemia and can evolve ”more or less insidiously ”into liver cirrhosis. Renal involvement affects about one-third of patients with mixed cryoglobulinemia. It takes the form of a membranoproliferative glomerulonephritis characterized clinically by proteinuria, which may evolve to an overt nephritis syndrome and, if not appropriately treated, end in renal failure.

      Other manifestation of mixed cryoglobulinemia are sensorimotor peripheral neuropathy, Raynaud's phenomenon , sicca syndrome, hyperviscosity syndrome, and lung involvement.

   2. Diagnosis. The diagnosis of cryoglobulinemia is based on the typical triad of symptoms: purpura, arthralgias, and weakness, and on the presence of type 2 cryoglobulins. Complement levels (C1, C2, C4) are low. Rheumatoid factor is present. Hepatitis B and C viruses frequently have been associated with mixed cryoglobulinemia.
   3. Treatment. Mixed cryoglobulinemia is characterized by a broad spectrum of clinical manifestations ranging from mild (arthralgia and weakness) to severe (renal involvement), and the course of disease is characterized by spontaneous remissions and exacerbations. As a consequence, no single treatment protocol can be established.

      For the minor clinical manifestations (arthralgias, purpura, arthritis), therapies aimed at treating the symptoms are sufficient: NSAIDs and low-dose corticosteroids (<10 mg of methylprednisolone daily). The major manifestations of mixed cryoglobulinemia (central nervous system involvement, kidney involvement, hyperviscosity syndrome) require more aggressive treatment, such as high-dose corticosteroids (1 mg/kg or pulse therapy), cytotoxic drugs (2 to 3 mg of cyclophosphamide per kilogram pulse therapy), or plasma exchange with or without immunosuppressive drugs. The aggressive use of cytotoxic agents is no longer recommended in view of their immunomodulatory properties and the potential to promote viral replication. Interferons have been used in the management of mixed cryoglobulinemia; in our experience interferon- b can have a positive effect. Controlled short-term trials have clearly shown that the interferons can reduce many of the signs (hepatitis C virus and cryoglobulin levels) and symptoms (purpura, abnormal liver enzymes), but its long-term effect on the natural history of the disease has not yet been established.

5. Leukemias. Rheumatic manifestations occur in a small percentage of adults with either acute or chronic leukemia, but they are common in children with acute lymphoblastic leukemias. In some cases, bone pain, arthralgias, and periarthritis are caused by leukemic infiltration of the periosteum, synovium, or periarticular bone and may predate the diagnosis of leukemia. The arthritis is asymmetric, additive, and polyarticular and the joint pain can be prominent at night. The knees, ankles, and shoulders are most commonly affected. In children, the association of arthritis and fever can mimic Still's disease. In hairy-cell leukemia, both polyarthritis and polyarteritis nodosa have been described. Symptomatic skeletal involvement is uncommon in the lymphomas, although bone lesions may be found at autopsy.

IV. Multicentric reticulohistiocytosis. Multicentric reticulohistiocytosis is a systemic disorder of unknown etiology characterized by the infiltration of tissues by histiocytes and multinucleated cells. It primarily affects the skin, mucous membranes, and joints. The disease has a worldwide distribution with a female predominance. It usually begins during the fourth decade of life with polyarthritis, cutaneous lesions, or concurrent arthritis and skin manifestations. Up to 25% of cases have been associated with malignancies, but the condition is not considered to be paraneoplastic.

1. Clinical picture. The polyarthritis is symmetric, progressive, and destructive, attacking the small and large peripheral joints. The joints most frequently affected are the interphalangeal joints of the hands including the DIP joints, shoulder, knee, wrist, hip, elbow, and spine. The clinical picture can mimic that of rheumatoid arthritis. In one-half of all patients, severely deforming arthritis mutilans may develop.

   The skin lesions are usually asymptomatic, discrete, firm, pinkish brown or purple, hemispheric, nonpruritic papulonodules that occasionally coalesce. They are most numerous over the dorsum of the hands, on the face, and behind the ears. Lesions of the buccal mucosa, nasal septum, or lips occur in about half of the patients with skin nodules. Involvement of bone, tendon sheath, muscle, liver, lung, and other organs has been reported but is not common.

   The course of disease is not well defined; it may be either mild and slow in progression or aggressive, and spontaneous remissions may be seen.

2. Diagnosis. The diagnosis is based on histology of the cutaneous nodules; characteristic findings are infiltration by histiocytes and large, multinucleated giants cells with a ground-glass appearance, which stain positively for lipids and glycoproteins (periodic acid “Schiff).

   The diagnosis of joint disease is usually indicated by radiographs showing extensive bone destruction rather than articular cartilage loss, and very mild osteopenia around the affected joints. The findings on joint fluid analysis may be quite variable; most often, the effusions are inflammatory. The erythrocyte sedimentation rate is normal or slightly raised, and rheumatoid factor is absent.

3. Treatment. Because of the flares and spontaneous remissions that characterize this disorder, the efficacy of different drug therapies is difficult to assess. Immunosuppressive drugs such as corticosteroids and cyclophosphamide have been claimed to be effective. Low-dose pulse methotrexate has also been shown to be useful as a maintenance therapy.

V. Pigmented villonodular synovitis (PVNS) is a rare disorder of unknown etiology characterized by a slowly progressive, yet potentially invasive, benign proliferation of the synovial tissue. It is more common in females than in males. The salient histologic features are the deposition of hemosiderin and the infiltration of histiocytes and giant cells in a fibrous stroma within the synovium of the tendon sheaths and large joints.

1. Clinical features. PVNS may present in three different clinical forms:
   1. Pigmented villonodular tenosynovitis (also referred to as giant cell tumor of the tendon sheath), the most common expression of PVNS, typically presents in adults and is more prevalent in women. The lesion is isolated, discrete, and usually painless but is slowly progressive and may cause erosion of the adjacent bone. The hand, especially the fingers, is the most common site of involvement.
   2. Diffuse intraarticular pigmented villonodular synovitis primarily affects young adults. It takes the form of a chronic monarticular arthropathy, with the knee being the most commonly involved joint, followed by the hip and ankle. Less frequently, the hand, shoulder, wrist, or vertebrae may be affected. Progression is slow, with initially intermittent and later persistent joint swelling and pain. Joint effusion is usually present. Histologically, the lesion resembles that of pigmented villonodular tenosynovitis. This form can mimic the chronic synovitis of rheumatoid arthritis.
   3. Localized pedunculated villonodular synovitis is the least common presentation of PVNS. The knee is the most frequently involved joint, the lesion being localized in the medial or lateral compartment . The patient presents with mechanical symptoms of locking and clicking. Synovial effusions may be slightly bloody.
2. Diagnosis. In both diffuse and localized joint synovitis, radiographs may show soft-tissue swelling without calcifications, a useful clue for the differential diagnosis from synovial osteochondromatosis. Osteophytes and juxtaarticular osteoporosis, typical of degenerative joint disease and rheumatoid arthritis, respectively, are absent. Sonography and MRI may show synovial proliferation. The diagnosis can be confirmed by arthroscopy and synovial biopsy, which show fibroblasts, giant cells, hemosiderin deposits, and areas of hemorrhaging with a mild inflammatory component.
3. Treatment. PVNS may be treated surgically, but recurrences are frequent. Radiotherapy, alone or in association with synovectomy, can reduce the risk for recurrence . Surgical excision in cases of the localized form involving the knee is usually more successful. Total arthroplasty is required when extensive joint destruction is present.

VI. Sarcoidosis. Sarcoidosis is a systemic disease of unknown etiology characterized by the presence of noncaseating granulomas of the involved tissue. The disease is most common in subjects 20 to 40 years of age and generally involves the lung, although any organ may be affected and the condition can mimic rheumatic disease. The sarcoid granuloma may arise in the lung (86% of patients); lymph nodes (86%); liver (86%); spleen (63%); heart, kidney, or bone marrow (17% to 20%); or pancreas (6%). The etiopathogenesis is unknown, but it appears that the cellular immune response plays a central role.

1. Clinical picture. The most frequent clinical manifestations of sarcoidosis are pulmonary symptoms, asymptomatic hilar adenopathy, constitutional symptoms, and extrathoracic manifestations, which may include rheumatologic manifestations.
   1. Pulmonary involvement. Pulmonary symptoms include dry cough, dyspnea, and chest pain; pleural effusions are rare. Four types of findings may be revealed on chest radiography: type 0, no abnormalities; type 1, enlargement of the hilar and mediastinal lymph nodes; type 2, adenopathy and pulmonary infiltrates; and type 3, infiltrates without adenopathy.
   2. Rheumatologic manifestations. Acute polyarthritis is the most common and is often the first manifestation of the disease. Erythema nodosum is strikingly associated with early arthritis.

      The association of acute arthritis, erythema nodosum, and bilateral hilar adenopathy is called Lofgren's syndrome; it has an excellent prognosis with a 90% remission rate. The acute arthritis is usually symmetric and generally involves the larger joints, especially the ankles and knees, although the small joints of the hands and feet and the shoulders, hips, wrist, and elbow can also be affected. Periarticular swelling is more common than joint effusions. When effusions occur, the synovial fluid is not inflammatory. The symptoms of arthritis may resolve in a few weeks or may persist for several months. Few patients suffer more than one isolated attack, however.

      The second form of arthritis that may occur in sarcoidosis appears 6 months or more after the onset of disease; the knee is the most frequently involved joint, followed by the ankles and proximal interphalangeal joints. Monarthritis can also occur. The arthritis may be transient or chronic and is not associated with erythema nodosum. The synovial fluid shows little or no signs of inflammation; synovial biopsy occasionally reveals granulomas. The chronic form often manifests as dactylitis. The symptoms of sarcoid dactylitis are swelling of the soft tissue over the affected digits, tenderness, and painful stiffness: the overlying skin may be erythematous. Radiographic changes are uncommon but destructive, and bone cystic changes can occur.

      Myopathy in sarcoidosis is rare; the affected patient may have a chronic, progressive muscle disease that resembles polymyositis or muscular dystrophy. Acute myositis and palpable nodules can occur. Muscle biopsy may reveal a sarcoid granuloma, even in the presence of asymptomatic muscle involvement. Other rheumatologic manifestations that may be associated with sarcoidosis include parotid gland enlargement and keratoconjunctivitis, similar to Sj gren's syndrome, or upper airway disease (sinusitis, laryngeal inflammation, saddle nose deformity), similar to Wegener's granulomatosis. Eye involvement is seen in about 22% of patients, anterior uveitis being more common than posterior uveitis.

      Other extrathoracic manifestations include peripheral lymphadenopathy, skin involvement (erythema nodosum, papules, nodules, plaques, lupus pernio), and renal and central nervous system involvement. Most patients have hepatic granulomas, but only 20% show hepatomegaly or elevated liver enzymes. Constitutional symptoms such as malaise, fever, and fatigue are often present.

2. Diagnosis. The diagnosis of sarcoidosis is made on the basis of the clinical findings, histologic evidence of noncaseating granulomas, and the exclusion of other diseases. Biopsy of lesions, scalene muscles, or mediastinal lymph nodes is necessary to confirm the diagnosis. Liver biopsy may also be helpful. Skin anergy is typical but not diagnostic. Bronchoalveolar lavage is another useful indicator, with specimens showing an increased number of T lymphocytes during active disease.

   Levels of ACE (angiotensin-converting enzyme ) inhibitor, produced by the cells of sarcoid granulomas, are elevated in two-thirds of all patients.

   A gallium citrate scan may show increased uptake in the pulmonary parenchyma; this is not specific for sarcoidosis but is helpful in following the disease activity and course, as well as the effects of therapy.

3. Treatment. The treatment may consist of short courses of corticosteroids at moderate doses (20 to 40 mg of methylprednisolone). Methotrexate and hydroxychloroquine can be used as a corticosteroid- sparing agent in patients with chronic disease. NSAIDs may be useful to treat acute episodes of arthritis.

   The disease course is generally mild, and treatment usually results in long-term remission. Chronic or aggressive disease develops in only a small number of patients and may demand equally aggressive immunosuppressive therapy.

VII. Storage diseases

1. Gaucher's disease. Gaucher's disease is an autosomal recessive disease resulting from the accumulation of glucocerebroside in organs and tissues, mainly throughout the reticuloendothelial system in characteristic storage cells (Gaucher's cells). The condition is caused by a deficiency of the lysosomal enzyme glucocerebrosidase.

   Clinically, patients with the disease may be divided into three subgroups. Rheumatologic manifestations may constitute the first symptoms in the neuropathic adult form (type 1) and in the juvenile form (type 3). Acute severe pain (bone crisis) may be accompanied by tenderness, swelling, erythema, and fever, thus resembling osteomyelitis (pseudo-osteomyelitis). Osteonecrosis of the hip and talus have been described. Pathologic fractures of the long bones and low back pain can also occur.

   1. Diagnosis. The diagnosis is established by bone marrow biopsy and analysis of the peripheral blood leukocytes for residual b -glucocerebrosidase and b -glucosidase activity.
   2. Treatment. The principal treatment is enzyme replacement therapy with macrophage- targeted glucocerebrosidase purified from human placental tissue. Other options include splenectomy for thrombocytopenia and total hip arthroplasty for osteonecrosis. The possible efficacy of bone marrow transplantation and organ transplantation for end-stage disease involving the failure of a single organ is presently being explored.
2. Fabry's disease. Fabry's disease is a lysosomal lipid storage disease in which glycosphingolipids accumulate in nerve cells, organs, skin, and osteoarticular tissue. It is a sex-linked disease caused by deficiency of the enzyme a -galactosidase. Rheumatologic features include painful crises of burning paresthesias of the extremities, and degenerative changes and flexion contractures of the distal interphalangeal joints of the fingers. Systemic features include renal disease with progressive renal failure and cardiovascular, cerebrovascular, and ocular disease.
3. Farber disease. Farber disease is a rare sphingolipidosis of early childhood caused by the accumulation of ceramide. The initial manifestations may include hoarseness of the voice secondary to thickened vocal cords and various rheumatologic manifestations (pain and swelling of the joints of the fingers, wrists, elbows, ankles, and knees; joint contractures; and nodular masses or tendon sheaths in the periarticular tissues). Death often occurs before the age of 2, usually from respiratory disease.

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Husby G. Amyloidosis and rheumatoid arthritis. Clin Exp Rheumatol 1985;3:173.

Liang G, Granston A. Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide and low dose pulse methotrexate. Arthritis Rheum 1996;39:171.

Olsson KS. Hemochromatosis. In: Klippel J, Dieppe PA, eds. Rheumatology, 2nd ed. St. Louis: Mosby “Year Book, 1998:1 “4.

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Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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