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Systemic Diseases in Which Arthritis Is a Feature
Arthritis, arthralgias, and myalgias can be significant features of several systemic diseases and may be the presenting symptoms for some of these disorders ( Table 254-1 ). Appropriate evaluation of these musculoskeletal symptoms, including selected laboratory tests and radiographs, can provide clues to the early diagnosis of these diseases. Synovial biopsies are rarely necessary but can be diagnostic. Because of the rarity of many of these diseases, evidence-based treatments with U.S. Food and Drug Administration–approved medications are lacking.
TABLE 254-1
SYSTEMIC DISEASES ASSOCIATED WITH ARTHRITIS
| DISEASE | TEST ∗ |
|---|---|
| GASTROINTESTINAL DISEASES | |
| Autoimmune hepatitis ( Chapter 135 ) | Liver-associated enzymes, ASMA |
| Primary biliary cirrhosis ( Chapter 141 ) | Alkaline phosphatase, antimitochondrial Ab |
| Inflammatory bowel disease ( Chapter 127 ) | Fecal occult blood testing, fecal calprotectin, colonoscopy |
| Whipple disease ( Chapter 305 ) | Tissue biopsy, tissue immunohistochemical stain for Tropheryma whipplei, PCR for T. whipplei DNA |
| Gluten-sensitive enteropathy ( Chapter 126 ) | Antitransglutaminase antibody, small bowel biopsy |
| Pancreatitis-arthritis syndrome ( Chapter 130 ) | Lipase, amylase, abdominal CT scan |
| Hepatitis B/hepatitis C ( Chapter 135 ) | Liver-associated enzymes, hepatitis serology, cryoglobulins |
| Intestinal bypass arthritis | Cryoglobulins |
| HEMATOLOGIC DISORDERS | |
| Hemophilia ( Chapter 160 ) Hemoglobinopathies ( Chapter 149 ) Hypogammaglobulinemia ( Chapter 231 ) Plasma cell dyscrasias ( Chapter 173 ) |
PTT, factor VIII and IX levels CBC, hemoglobin electrophoresis Low total protein, SPEP, immunoglobulins High total protein, SPEP, UPEP, IEF |
| ENDOCRINE DISORDERS | |
| Diabetes mellitus ( Chapter 210 ) Thyroid disorders ( Chapter 207 ) Parathyroid disorders ( Chapter 227 ) Acromegaly ( Chapter 205 ) Hyperlipoproteinemia ( Chapter 190 ) Paget disease ( Chapter 228 ) |
Glucose, hemoglobin A 1c TSH, thyroxine Calcium, phosphorus, PTH Radiographs, growth hormone, IGF-I Lipid panel Bone-specific alkaline phosphatase, radiographs, bone scan |
| MALIGNANT DISORDERS | |
| Hypertrophic osteoarthropathy | Radiographs (hands, wrists, chest) |
| Leukemia and lymphoma ( Chapters 168 to 172 ) | CBC, LDH, bone marrow/tissue biopsy |
| Carcinomatous polyarthritis | Cancer screen |
| Palmar fasciitis and arthritis | CA-125, pelvic CT scan, cancer screen |
| OTHER DISEASES | |
| Hemochromatosis ( Chapter 196 ) | Iron studies, radiographs, HFE gene |
| Multicentric reticulohistiocytosis ( Chapter 155 ) | Radiographs, skin/synovial biopsy |
| Sarcoidosis ( Chapter 83 ) | Chest radiograph, ACE level, tissue biopsy |
| IgG4-related disease | Serum IgG4 level, histopathology of biopsy specimens including IgG4 immunostaining |
| Alkaptonuria ( Chapter 189 ) | Radiographs, urine homogentisic acid level |
| Fabry disease ( Chapter 191 ) | Angiokeratomas, a -galactosidase A level or gene mutation |
| Relapsing polychondritis ( Chapter 239 ) | Cartilage biopsy |
| Cystic fibrosis ( Chapter 77 ) | Chest radiograph, sweat chloride, CFTR gene mutation |
| Tenosynovial giant cell tumor: diffuse type (diffuse pigmented villonodular synovitis) | Synovial fluid analysis, MRI, synovial biopsy |
| Systemic infections | Cultures, serologies (RPR, HIV, EBV, parvovirus) |
Ab = antibody; ACE = angiotensin-converting enzyme; ASMA = anti–smooth muscle antibody; CBC = complete blood cell count; CFTR = cystic fibrosis transmembrane conductance regulator; CT = computed tomography; EBV = Epstein-Barr virus; HIV = human immunodeficiency virus; IEF = immunoelectrophoresis; IGF-I= insulin-like growth factor-I; IgG4 = immunoglobulin G4; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PTH = parathyroid hormone; PTT = partial thromboplastin time; RPR = rapid plasmin reagin; SPEP = serum protein electrophoresis; TSH = thyroid-stimulating hormone; UPEP = urine protein electrophoresis.
∗ Tests listed are common laboratory tests and radiographs that are frequently ordered; this information should provide a clue that a systemic disease is a possible cause of the patient’s musculoskeletal symptoms. These tests, coupled with the history and physical examination, should be followed by more specific tests and biopsies (listed in italics) to confirm the diagnosis.
Autoimmune Hepatitis
Patients with type I autoimmune hepatitis ( Chapter 135 ) may present with a syndrome resembling systemic lupus erythematosus ( Chapter 245 ). Patients with the early-onset subset are frequently young and female, with complaints of polyarthralgia and occasionally various rashes and/or fever. Laboratory examination may show leukopenia, a positive antinuclear antibody (70 to 90%), elevated erythrocyte sedimentation rate, polyclonal gammopathy, and elevated liver-associated enzymes. Hypocomplementemia and antibodies against double-stranded DNA are usually not seen, whereas antibodies against the smooth muscle antigen (F1 actin) support the diagnosis. Joint radiographs show soft tissue swelling without erosions or deformity. Joint pain resolves with corticosteroid therapy for the liver disease. Patients with autoimmune hepatitis have an increased risk for having a concurrent autoimmune disease, including Sjögren syndrome ( Chapter 247 ), in about 7% of cases.
Primary Biliary Cholangitis (Cirrhosis)
Up to 50% of patients with primary biliary cholangitis (PBC) ( Chapter 141 ) have other autoimmune disorders, including rheumatoid arthritis, Sjögren syndrome, limited systemic sclerosis, systemic lupus erythematosus, and autoimmune thyroiditis. In addition to antimitochondrial antibodies, rheumatoid factor, antinuclear antibodies, and anticentromere antibodies are often present. More than 10% of patients with primary biliary cholangitis have a symmetrical or asymmetrical small joint inflammatory arthritis. Unlike rheumatoid arthritis, it can involve distal interphalangeal joints and is rarely erosive or deforming. Other musculoskeletal manifestations include osteomalacia related to vitamin D deficiency, osteoporosis related to renal tubular acidosis, and hypertrophic osteoarthropathy associated with liver disease.
Inflammatory Bowel Disease
Musculoskeletal symptoms are the most frequent extraintestinal manifestation occurring in patients with inflammatory bowel disease (ulcerative colitis and Crohn disease; Chapter 127 ). The pathogenesis of these musculoskeletal manifestations is complex and includes interactions among gut microbes, mucosal immunity, and a genetic predisposition. Symptoms occur most commonly in patients who have involvement of the large bowel. Two types of inflammatory peripheral arthritis occur in about 15% of patients. Type I arthropathy is an acute, remitting (<6 months), nondestructive oligoarthritis most commonly involving the knee. This arthritis occurs early or prior to onset of bowel symptoms and is often associated with flares of inflammatory bowel disease. Type II arthropathy tends to be a nondestructive polyarthritis involving both small (e.g., metacarpophalangeal) and large joints. This arthritis persists for months, has frequent relapses, and does not parallel the activity of inflammatory bowel disease. Sacroiliitis (10%) and ankylosing spondylitis (3%) present with buttock and spinal pain and stiffness. This axial spondyloarthropathy, which can occur alone or in association with type I arthropathy, is associated with HLA-B27 (in 50 to 75% of cases), and its clinical course is not related to the activity of the inflammatory bowel disease. Other possible rheumatic manifestations include dactylitis (0 to 6%), enthesitis, septic arthritis, and hypertrophic osteoarthropathy. Treatment of the underlying inflammatory bowel disease, including conventional synthetic and/or biologic disease-modifying drugs ( Chapter 123 ), will improve the musculoskeletal manifestations.
Whipple Disease
An inflammatory arthritis occurs in up to 80% of patients with Whipple disease ( Chapter 305 ) and may precede the gastrointestinal manifestations by a median of 5.5 years. The joint involvement is typically an intermittent, migratory oligoarthritis, which affects large joints more than small joints or the sacroiliac joints and which persists from several hours to days. The synovial fluid is inflammatory, with a predominance of mononuclear cells. Subcutaneous nodules are occasionally seen and may lead to an erroneous diagnosis of rheumatic fever or rheumatoid arthritis. However, patients consistently test negative for rheumatoid factor and antinuclear antibodies. Synovial biopsies show rod-shaped bacilli on electron microscopy, which have been identified as Tropheryma whipplei . Diagnosis is suspected when duodenal, synovial, or lymph node biopsies show periodic acid–Schiff–positive macrophages. Infection is confirmed by demonstration of the organism in tissue by immunohistochemical staining with antisera specific for T. whipplei . Quantitative polymerase chain reaction to detect T. whipplei DNA is used as a confirmatory test performed on tissue and body fluids. Typically, the arthritis does not cause radiographic changes or deformities. Prolonged antibiotic therapy results in resolution of musculoskeletal as well as other symptoms of this disease. Relapses, especially neurologic, can occur in up to 35% of patients after cessation of antibiotic therapy.
Gluten-Sensitive Enteropathy (Celiac Disease)
An asymmetrical oligoarthritis or symmetrical polyarthritis occurs in up to 25% of adults with celiac disease ( Chapter 126 ). The arthritis may precede the enteropathic symptoms by months to years in up to 50% of cases. Large joints such as knees and ankles, more than hips and shoulders, are most commonly involved. Axial involvement is reported. The arthritis does not cause deformities or radiographic changes and resolves with a gluten-free diet in 40 to 50% of cases. Another musculoskeletal manifestation is osteomalacia ( Chapter 226 ) related to vitamin D malabsorption, which may mimic diffuse fibromyalgia. Arthralgias due to gluten sensitivity without celiac disease are also reported.
Pancreatitis-Arthritis Syndrome
Pancreatic panniculitis is a systemic syndrome occurring in some patients with pancreatic acinar cell carcinoma ( Chapter 180 ) and less commonly in patients with pancreatitis ( Chapter 130 ) or hematologic malignancies. Prominent fat necrosis is due to the release of lipase, amylase, and trypsin from the diseased pancreas. This syndrome is characterized by tender red nodules, usually on the extremities; these lesions are frequently misdiagnosed as erythema nodosum, but biopsy shows areas of lobular panniculitis with fat necrosis. Arthritis occurs in 60% of patients and usually involves the ankles and knees. Other manifestations include osteolytic lesions (10%) from bone marrow fat necrosis, pleuropericarditis, fever, and eosinophilia. Magnetic resonance imaging (MRI) shows multifocal intraosseous fat necrosis and arthritis of the knees and feet. Synovial fluid is typically noninflammatory and creamy in color. It contains multiple lipid droplets because of necrosis of fat in the synovial membrane.
Hemophilia
Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) ( Chapter 160 ) are associated with hemarthrosis. Acute and chronic arthritis are less frequent and less severe in patients with hemophilia B compared with hemophilia A. Almost all patients with factor levels less than 1% of normal experience recurrent hemarthroses spontaneously or after minor trauma. Large joints (knees, elbows, ankles) are most commonly involved. Intramuscular hemorrhage can also occur. Recurrent hemarthrosis can lead to proliferative synovitis and cartilage degradation, thereby resulting in both erosive and degenerative changes on radiographs or ultrasonography. Physical examination shows bone enlargement, crepitus, atrophic muscles, and joint contractures. Treatment of acute monoarthritis consists of factor replacement to achieve a level of 30% or greater, given at the first sign of joint swelling. Patients with fever (temperature >38° C) or who fail to respond to factor replacement need joint aspiration to exclude septic arthritis, which occurs with an increased incidence in hemophilia. Chronic arthritis is treated with COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs; Table 26-4 ), which do not inhibit platelet function; arthroscopic or radiation synovectomy for chronic synovitis; and total joint arthroplasty for end-stage joint disease. Better preventative therapies have reduced the risk for developing chronic arthropathy.
Hemoglobinopathies
Patients with sickle cell anemia ( Chapter 149 ) or the heterozygous states of sickle β-thalassemia and sickle hemoglobin C disease frequently experience polyarthralgia. Local sickling of cells leads to obstruction of the microcirculation and to bone infarctions. Patients most commonly experience painful crises causing chest, back, and joint pain, which can be caused or worsened by glucocorticoid therapy. A painful large joint arthritis (usually in the knees), which persists for days to 3 weeks, can also occur. Synovial effusions are usually noninflammatory but can be mildly inflammatory because of local phagocytosis of sickled cells. Infarcts in the metaphyses of bones are commonly found on joint radiographs. Vertebral bodies have a characteristic “Lincoln log” appearance or a central cuplike indentation (“codfish vertebrae”). Femoral and humeral head osteonecrosis can occur in up to 33% of patients with sickle cell anemia and sickle hemoglobin C disease. Because of splenic autoinfarction, septic arthritis ( Staphylococcus aureus ) and osteomyelitis (50% caused by Salmonella ) have been associated with sickle cell disease. In adults, gout has been reported. Treatment includes intravenous hydration, oxygen, and analgesics. Hydroxyurea can reduce the frequency of painful crises. In patients with β-thalassemia major ( Chapter 148 ), significant expansion of bone marrow, owing to increased erythroid precursors, leads to osteoporosis and microfractures that affect primarily the lower extremities. Chelation therapy with deferiprone to reduce iron overload from transfusions can cause arthralgias in 20% of patients.
Hypogammaglobulinemia
Common variable immunodeficiency and selective immunoglobulin A (IgA) deficiency are the most common primary immunodeficiencies ( Chapter 231 ). Adults with common variable immunodeficiency can develop a nonerosive, noninfectious large joint oligoarthritis that responds to intravenous immunoglobulin therapy. However, septic arthritis caused by common pathogens or Mycoplasma can also occur and must be rigorously excluded. Autoimmune disorders, most commonly autoimmune cytopenias and pernicious anemia, occur in 30% of patients with common variable immunodeficiency and may be the presenting manifestation. Selective IgA deficiency ( Chapter 231 ) is associated with various rheumatic manifestations, including positive autoantibodies, in the absence of clinical disease. Systemic autoimmune disorders, including systemic lupus erythematosus and organ-specific autoimmune disorders, such as type 1 diabetes mellitus and myasthenia gravis, also occur in IgA-deficient individuals.
Amyloidosis
Primary amyloidosis and myeloma-associated amyloidosis are plasma cell disorders with overproduction of monoclonal immunoglobulin light chains ( Chapter 174 ) and their deposition in tissues. Amyloid deposits in the synovium can lead to rheumatic symptoms, which may be misdiagnosed as rheumatoid arthritis or polymyalgia rheumatica. Amyloid arthropathy occurs in up to 5% of myeloma patients and may be the initial manifestation. Arthropathy affects both males and females at an average age of 60 years. Polyarthritis or oligoarthritis most commonly affects the shoulders, knees, wrists, and small joints of the hand. Subcutaneous nodules and carpal tunnel syndrome can be additional manifestations. The erythrocyte sedimentation rate is nearly always elevated, but rheumatoid factor and antinuclear antibodies are negative. Synovial fluid is usually normal or minimally inflammatory. Congo red staining of spun synovial fluid can show amyloid deposits from synovial fragments. Joint radiographs are nonerosive but may show lytic bone lesions. The arthritic symptoms do not respond to glucocorticoids or other anti-inflammatory medications.
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