Box 30.1 COMMON LABORATORY ABNORMALITIES ASSOCIATED WITH INFLAMMATION

Box 30.2 SIDE EFFECTS OF SYSTEMIC CORTICOSTEROIDS

POLYMYALGIA RHEUMATICA

Polymyalgia rheumatica (PMR) is a systemic inflammatory disorder of individuals older than age 50. It typically presents as limb-girdle achiness of the shoulders and hips out of proportion to examination findings, with a preponderance of morning stiffness. Presentation is usually sudden in onset and is rarely associated with synovitis of the small joints. Laboratory tests show evidence of systemic inflammation (box 30.1). Erythrocyte sedimentation rate (ESR) may be >100 mm/hour. Few other disease states are associated with such an elevated ESR (box 30.3). Up to 5–10% of patients with PMR will evolve into an illness that resembles RA. Up to 15–20% of patients with PMR will develop symptoms of giant-cell arteritis (discussed below). Low-dose corticosteroids (<15 mg daily) are the primary treatment for PMR. Steroids are tapered as symptoms allow, sometimes over 1–2 years.

Box 30.3 DIFFERENTIAL DIAGNOSIS OF DISEASES ASSOCIATED WITH AN ERYTHROCYTE SEDIMENTATION RATE >100 MM/HOUR

SPONDYLOARTHROPATHIES

The spondyloarthropathies are a collection of disorders that include ankylosing spondylitis, psoriatic arthritis, arthropathy associated with inflammatory bowel disease (IBD arthropathy), postinfectious (reactive) arthritis, and undifferentiated spondyloarthropathy. Unlike RA, peripheral arthritis is typically oligoarticular, asymmetric, and most pronounced in the lower extremities. Further distinguishing features of spondyloarthropathies include lumbosacral inflammation (spondylitis or sacroiliitis), enthesitis, and bone-forming lesions by radiography. Morning back stiffness in a young person should alert the clinician to the possibility of inflammatory back disease.

    Ankylosing spondylitis (AS) has a >3:1 male-to-female predominance. AS primarily affects the spine and can lead to fusion (ankylosis) of the vertebrae. Women may develop AS in an atypical fashion with neck involvement before spine and sacroiliac (SI) joint involvement. Psoriatic arthritis and IBD arthropathy are associated with their respective disease entities, but spine involvement can cause “skip areas” rather than a uniform progression as one sees in AS. Arthritis may precede the skin or bowel disease in these disorders. Reactive arthritis is associated with antecedent infection by chlamydia or enteroinvasive bowel pathogens (Shigella, Salmonella, or Yersinia). Additional extra-articular manifestations of all the spondyloarthropathies may include dactylitis (“sausage digit”), uveitis, circinate balanitis, and scaly plantar lesions (keratoderma blennorrhagica). Rarely, these conditions are associated with proximal aortic aneurisms and pulmonary fibrosis.

    Laboratory workup of the spondyloarthropathies fails to reveal antinuclear antibodies (ANA), RF, or anti-CCP antibodies. Although nonspecific, laboratory tests may show systemic inflammation (box 30.1), and synovial fluid white blood cell (WBC) may be extremely elevated. Spinal involvement is closely associated with HLA-B27, but the diagnostic utility of testing HLA status is debatable, although newer criteria incorporate this test. Enthesitis, ankylosis, and sacroiliitis are hallmark radiographic findings. The treatment of the spondyloarthropathies closely mirrors that of RA. Traditional DMARD therapies (methotrexate and sulfasalazine) only have a role in the treatment of peripheral inflammatory spondyloarthritis; they are ineffective for spine disease. On the contrary, TNF-α antagonists are uniquely effective in the treatment of spinal manifestations of the spondyloarthropathies.

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized primarily by constitutional symptoms, hematologic abnormalities, and immune complex deposition in target organs. It tends to afflict women of childbearing age. Some patients with an inherited deficiency of complement are at increased risk to develop SLE. The potential manifestations of SLE are myriad (table 30.1), and the diagnosis of SLE requires a strong clinical suspicion, laboratory or pathologic evidence of disease, and exclusion of other possible infectious, rheumatic, and neoplastic conditions. Even in patients with established SLE, new clinical symptoms should not be reflexively attributed to SLE. Medication reactions and opportunistic infections occur commonly, and noninflammatory joint pain may indicate superimposed fibromyalgia or avascular necrosis (AVN; see box 30.4).

    Lupus nephritis is the principal renal manifestation of SLE and is characterized by proteinuria and hematuria with red blood cell casts. Disease severity is classified based on histologic assessment of renal biopsy. Please see box 25.1, for the World Health Organization (WHO) classification of SLE nephritis. The degree of pathologic renal involvement cannot be predicted adequately by clinical criteria alone. Despite treatment, some patients still progress to end-stage renal disease (ESRD) and require dialysis therapy or renal transplantation. Renal vein thrombosis, interstitial nephritis, and antiphospholipid syndrome (APS) may also lead to renal dysfunction in patients with SLE.

    Autoantibody formation is the hallmark immunologic signature of SLE. ANA is detectable in essentially 100% of patients with SLE, but this test lacks specificity. Many other inflammatory conditions and upward of 20% of healthy patients may have a “positive ANA.” Anti–double-stranded DNA (dsDNA) and anti-Smith antibody testing are much more specific but less sensitive assays. Anti-Ro (anti-SSA), anti-La (anti-SSB), and anti-ribonuclear protein (anti-RNP) antibodies may also be detectable in patients with SLE. A prevailing opinion is that these antibodies form circulating immune complexes that deposit in target tissues, recruit complement and other immunologic mediators, and cause end-organ disease.

Box 30.4 RISK FACTORS FOR AVASCULAR NECROSIS (AVN) IN ADULTS

    Corticosteroids remain the mainstay of treatment in acute SLE flares. High doses (1 mg/kg prednisone or equivalent) are often used for severe hematologic abnormalities or organ-threatening disease. Lower doses of corticosteroids or NSAIDs are often sufficient for cutaneous, musculoskeletal, and serositis manifestations. Steroid-sparing agents are used to minimize steroid-related complications. Other than corticosteroids, only hydroxychloroquine and belimumab, a new biologic agent, have been approved for use in SLE by the United States Food and Drug Administration. Regardless, many other immunosuppressive and cytotoxic medications have been used successfully in the treatment of SLE: azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, and possibly rituximab. Antimalarial agents (e.g., hydroxychloroquine) are well-tolerated drugs that play an important role in the treatment of SLE through poorly understood mechanisms. Methotrexate is particularly useful in the treatment of cutaneous, musculoskeletal, and serositis manifestations of SLE. Belimumab is effective mostly for cutaneous and musculoskeletal features of SLE. Azathioprine and mycophenolate mofetil have proven efficacy in the treatment of lupus nephritis. Cyclophosphamide is a cytotoxic agent reserved for the most severe manifestations of SLE (e.g., severe nephritis, pulmonary hemorrhage, severe central nervous system (CNS) disease, vasculitis). Acute complications of cyclophosphamide include hemorrhagic cystitis, bone marrow suppression, infertility, and profound immunosuppression. Lymphoma and urinary tract cancers are potential long-term adverse events. Plasmapheresis and intravenous immunoglobulin (IVIG) may be added to immunosuppressive therapy for life-threatening SLE. Anticoagulation is used in patients with thrombotic complications.

    APS is a hypercoagulable state in which a patient suffers a clot or fetal loss in the setting of having detectable serum antiphospholipid antibodies measured on two separate tests at least 12 weeks apart. Clots may be either venous, arterial, or even microvascular in nature. Fetal loss includes any three or more first-trimester miscarriages or any fetal loss after the first trimester. Antiphospholipid antibodies include anticardiolipin antibodies (IgG or IgM), antiprothrombin antibodies, anti-beta-2-glycoprotein I antibodies, or the lupus anticoagulant, which elevates the partial thromboplastin time (PTT) and is not corrected on mixing with normal serum. The term “secondary APS” describes disease that occurs in the presence of an underlying autoimmune disease, most commonly SLE, whereas no such disorder is detected in “primary APLS.” Catastrophic APLS is the syndrome of APLS with multiple clots, microvascular thrombosis, and organ failure. It has a mortality rate reported as 50% or greater. All manifestations of APS are treated with anticoagulation. Immunosuppression may also be used, and plasmapheresis may be added in cases of refractory APS or catastrophic APS.

    Finally, drug-induced lupus (DIL) may occur with use of hydralazine, procainamide, isoniazid, methyldopa, quinidine, minocycline, or even anti-TNF-α agents. It is characterized primarily by constitutional symptoms, mucocutaneous findings, serositis, and elevated ANA. Organ-threatening disease should prompt consideration of an alternative diagnosis. Antihistone antibodies are a sensitive but not specific marker for DIL. Symptoms generally resolve after elimination of the offending drug.

SCLERODERMA

Scleroderma describes a family of rare but related disorders that share in common idiopathic dermal fibrosis. Scleroderma is categorized into localized disease (morphea and linear scleroderma) and systemic sclerosis (SSC). SSC is a disease characterized by both fibrosis and vasculopathy. SSC is subdivided into limited or diffuse disease based on the extent of fibrosis. In limited SSC, dermal fibrosis is restricted to the hands, feet, and face. Involvement of the proximal extremities or trunk indicates diffuse SSC. Organ fibrosis represents a major source of mortality. It occurs principally in the lungs, heart, and GI tract. Vasculopathy accounts for pulmonary hypertension, scleroderma renal crisis, and the nearly universal Raynaud’s phenomenon. Patients with SSC may manifest with the CREST symptoms (calcinosis cutis, Raynaud’s, esophageal dysmotility, sclerodactyly, and telangiectasia), which have a high risk of developing pulmonary hypertension and can also occur independently of SSC. Patients with SSC often have ANA positivity, and more specific autoantibodies may also be present. Anti-centromere antibodies are associated with limited SSC, CREST, and pulmonary hypertension. Anti-SCL70 antibodies are associated with diffuse SSC and cardiopulmonary fibrosis. Anti-RNA-polymerase-3 antibodies are associated with rapidly progressive cutaneous SSC and renal crisis.

    Treatment options exist for the vascular complications of SSC. Scleroderma renal crisis presents as hypertension, hematuria, and renal failure. Despite renal failure, renal crisis is treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or both. Aggressive use of these drugs to lower blood pressure has changed the natural history of scleroderma renal crisis such that patients may recover from or even avoid dialysis therapy. Pulmonary hypertension and digit-threatening Raynaud’s disease are treated with vasodilator therapies. Dihydropyridine calcium channel blockers may be effective, but endothelin receptor antagonists (e.g., bosentan), phosphodiesterase inhibitors (e.g., sildenafil), and prostacyclins have markedly reduced mortality from pulmonary hypertension.

    Pharmacologic treatment of fibrotic complications is sorely lacking. Immunosuppressive agents, including cyclophosphamide, have been used for pulmonary fibrosis, with only modest improvement in outcome. Additional therapy is symptom-directed. High-dose proton pump inhibitors are used for gastroesophageal reflux disease and should be administered to all patients with SSC to decrease the risk of esophageal strictures. Promotility agents (e.g., metoclopramide, erythromycin) are used for GI dysmotility, and oral antibiotics are used for bowel overgrowth syndrome.

    Several other syndromes may cause cutaneous or systemic fibrosis and should be considered in the differential diagnosis of SSC. Eosinophilic fasciitis causes cutaneous fibrosis and results from infiltration of eosinophils into subcutaneous fascia. Graft-versus-host disease causes cutaneous and bowel fibrosis. Nephrogenic systemic fibrosis occurs in patients with severe renal insufficiency exposed to gadolinium-based contrast agents often used in MRI procedures.

OTHER CONNECTIVE TISSUE DISEASES

Sjögren Syndrome

Sjögren syndrome (SS) may be a primary entity or may exist secondary to other CTDs such as SLE, RA, and SSC. Sicca describes the most predominant features of SS; dry mouth and dry eyes result from autoimmune destruction of salivary and lacrimal glands. Patients with SS often have positive ANA, anti-Ro, and anti-La antibodies, an elevated RF, and hypergammaglobulinemia. More serious complications include small-vessel vasculitis, polyarthritis, peripheral neuropathies, interstitial lung disease, and lymphoma. Lymphomas typically occur in mucosal-associated lymphoid tissue and are heralded by a monoclonal gammopathy and drop in RF titer. Treatment for SS is typically directed at symptoms with artificial saliva and tears. Vasculitis or ILD requires high-dose corticosteroids or other intensive immunosuppressive therapies like cyclophosphamide, which may increase the risk of lymphoma in these patients.

Idiopathic Inflammatory Myopathies

The idiopathic inflammatory myopathies (IIMs) include a collection of autoimmune diseases: dermatomyositis (DM), polymyositis (PM), malignancy-associated myositis, juvenile DM, and inclusion-body myositis (IBM). With the exclusion of IBM, these conditions present as proximal muscle weakness. Creatine kinase (CK) is typically elevated at least 5–10 times the upper limit of normal, and aldolase may also be elevated. DM, malignancy-associated myositis, and juvenile DM may have cutaneous manifestations. These include a malar rash that, unlike SLE, involves the nasolabial folds, a periorbital violaceous heliotrope rash, a photosensitive shawl sign over the precordium, Gottron papules over the dorsal knuckles, and hyperkeratotic mechanic’s hands. Interstitial lung disease may occur, usually in patients with anti-Jo-1 antibody. Oropharyngeal involvement may be life-threatening because of aspiration risk. Diagnosis is aided by MRI or electromyography (EMG). Muscle biopsy can confirm the diagnosis, showing an inflammatory infiltrate. Treatment consists primarily of high-dose corticosteroids, with additional immunosuppressive agents (e.g., methotrexate, azathioprine, IVIG, or possibly rituximab) in patients who are unable to taper corticosteroids. Unlike the other IIMs, IBM presents as distal muscle weakness and atrophy in elderly patients. Diagnosis is made by electron microscopy of a muscle biopsy. Treatment is generally ineffective.

Adult-Onset Still’s Disease

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease characterized by high fever, antecedent sore throat, evanescent rash, lymphadenopathy, hepatosplenomegaly, inflammatory arthritis, elevated liver transaminases, neutrophilic leukocytosis, and markedly abnormal laboratory markers of inflammation, especially ferritin (table 30.1). It is a diagnosis of exclusion after ruling out RA, SLE, infectious, and malignant diseases. Treatment is similar to that of RA but may require higher doses of steroids. Notably, AOSD may respond rather dramatically to the IL-1 receptor antagonist anakinra or the anti-IL-6 receptor antibody tocilizumab.

Mixed Connective Tissue Disease

Mixed connective tissue disease (MCTD) is an example of an overlap syndrome that manifests with various elements of several autoimmune diseases. Features may include inflammatory arthritis, sclerodactyly, Raynaud’s syndrome, inflammatory myositis, pulmonary hypertension, and secondary Sjögren syndrome. Serology is notable for a very high-titer ANA and detectable anti-RNP antibody. Treatment is directed at the individual manifestations.

THE VASCULITIDES

Collectively, the vasculitides represent a collection of diseases characterized by inflammation of blood vessels. The vasculitides are often categorized based on their involvement of large, medium, or small vessels (table 30.2). Patient demographics and serologic analysis are additional distinguishing features. Most vasculitides are serious conditions that are organ- or life-threatening. Fevers, constitutional symptoms, and abnormal inflammatory markers (box 30.1) are common features of most vasculitides. A definitive diagnosis often requires biopsy evidence of vascular inflammation. Immunosuppression with corticosteroids is a mainstay of treatment. Steroid-sparing agents (azathioprine, methotrexate, mycophenolate mofetil, rituximab) or cytotoxic agents (cyclophosphamide) are often added to limit steroid toxicity and provide additional immunosuppression. For the most part, TNF-α blockers are ineffective in systemic vasculitis.

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