Connective Tissue Diseases

Learning Objectives

Cite the appropriate laboratory tests for patients with suspected connective tissue disease (CTD).
Describe the interpretation of antinuclear antibody test results and indications for further testing based on patient symptoms.
Cite common adverse effects of drugs used to treat CTD.
Summarize when the use of tumor necrosis factor inhibitors is the preferred treatment for CTD.
Diagnose systemic lupus erythematosus (SLE) using appropriate laboratory tests in patients with typical symptoms.
Describe treatment for SLE and how to make appropriate and timely referrals to rheumatology subspecialists.
Describe drug treatment for lupus nephritis.
Summarize the diagnostic criteria for scleroderma.
Describe drug treatment for Raynaud phenomenon.

Key Practice Recommendations

In patients with suspected connective tissue disease, after a positive antinuclear antibody test result, obtain further testing for specific nuclear antigens, such as double-stranded DNA, Smith, ribonucleoprotein, Sjögren syndrome A, Sjögren syndrome B, Scl-70, and Jo-1, based on clinical circumstances that raise suspicion of specific diseases.
For treatment of mild symptoms in systemic lupus erythematosus, such as cutaneous manifestations and arthralgia, prescribe hydroxychloroquine and nonsteroidal anti-inflammatory drugs. When these drugs are ineffective or when the patient has fatigue or fever, add a low dose of corticosteroids.
Treat lupus nephritis either with the classic regimen of monthly cyclophosphamide combined with steroids or with mycophenolate mofetil.
When calcium channel blockers are ineffective as a treatment for Raynaud phenomenon in patients with scleroderma, treat with intravenous iloprost.

Resources

Strength of evidence: SORT C
Source: Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med. 2000;124(1):71-81.

Web site: http://www.archivesofpathology.org/doi/full/10.1043/0003-9985%282000%29124%3C0071%3AGFCUOT%3E2.0.CO%3B2
Strength of evidence: SORT A
Source: Finnish Medical Society Duodecim. Systemic lupus erythematosus (SLE). EBM Guidelines. Evidence-Based Medicine. Helsinki, Finland: Wiley Interscience; 2007. National Guideline Clearinghouse.

Web site: http://www.guidelines.gov/content.aspx?id=11047#Section420
Strength of evidence: SORT A
Source: Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev. 2004;(1):CD002922; Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353(21):2219-2228.

Web site: http://www2.cochrane.org/reviews/en/ab002922.html
Strength of evidence: SORT A
Source: Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev. 2000;(2):CD000953.

Web site: http://www2.cochrane.org/reviews/en/ab000953.html

AAFP FP Essentials^™ Approved as CME Clinical Content

This activity, FP Essentials^™, has been reviewed and is acceptable for up to 60 Prescribed credit(s) by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2010. This activity conforms to the AAFP criteria for evidence-based CME clinical content. Term of approval is for two year(s) from this date with the option of yearly renewal. Each monograph is approved for 5 Prescribed credit(s). Credit may be claimed for 2 years from the date of each monograph.

The evidence-based CME for this activity was based on a current clinical question that identifies gaps in learners’ knowledge, competency and/or performance in medical practice as identified in the current evidence available at the time this activity was approved. Since clinical research is ongoing and new evidence to supporting practice improvement is constant, the AAFP recommends that learners verify sources and review these as well as practice recommendations prior to implementation into practice.

Author Information

Daniel Muller, MD, PhD, is an associate professor in the Department of Medicine, Rheumatology division, at the University of Wisconsin, Madison, School of Medicine and Public Health. Dr Muller completed internal medicine and rheumatology fellowships, and has been involved in bench and clinical research and medical school curriculum development. He teaches undergraduate, graduate, and medical students and has authored more than 50 articles and book chapters on immunology and autoimmune diseases.

Disclosure: According to AAFP policy, authors must disclose all associations with proprietary entities that may have a direct relationship to the subject matter of their manuscript. The author and staff have returned disclosure forms indicating that they have no such affiliation or financial interest to disclose. The AAFP uses an anonymous peer review process to evaluate the content of this activity. This process ensures a clear resolution of any potential conflicts of interest, and guarantees the fairness and balance of the content.

Foreword

Much has changed in recent years in the diagnosis and management of connective tissue disease (CTD). It seems as if each time I ask a rheumatology subspecialist to see a patient who might have such a condition, the consultant wants to order new tests I’ve never heard of, or treat the patient with drugs I’ve never used.

In this edition of FP Essentials^™, Dr Dan Muller brings us up to date on these tests and drugs. In Section One, he takes us through all the old and new tests used in the diagnosis of CTD. In Section Two, he reviews key points about the various drugs used to treat these diseases. Then in Sections Three and Four, he provides a review of the current diagnosis and management of 2 of the more well-known CTDs—systemic lupus erythematosus and scleroderma. The most common of them all, rheumatoid arthritis, was reviewed in last April’s edition of FP Essentials, Arthritis Update.

I hope you learn as much from this edition as I did.

Barry D Weiss, MD, FAAFP, Medical Editor
Professor of Family and Community Medicine
University of Arizona College of Medicine, Tucson

Preface

All physicians will encounter patients with connective tissue diseases (CTDs). Rheumatoid arthritis is present in 1% of the population.1 Systemic lupus erythematosus (SLE) is present in 0.1% of the population, but is approximately ninefold more common in women.2 It is prevalent enough for most physicians to see many patients with SLE during the course of their careers. Scleroderma is much less common, present in approximately 0.025% of the population.3 However, physicians will sometimes encounter patients with Raynaud phenomenon and skin changes that might be related to scleroderma.

This edition of FP Essentials^™ provides updated information about the diagnosis and treatment of CTDs, reviews new diagnostic tests and drugs for CTDs, and provides updates on SLE and scleroderma. Whereas most physicians will monitor patients with these conditions in consultation with rheumatology subspecialists, family physicians often are the first to see patients with CTDs and frequently make the initial diagnosis. After the diagnosis is confirmed, patients with CTDs will be treated with multiple drugs with myriad possible adverse effects that should be known and recognized by family physicians.

SECTION ONE

New Diagnostic Tests

Case 1. Juan is a 40-year-old Hispanic man who presents to your office after being evaluated in the emergency department (ED) last night for pain and inflammation in the joints of both hands. He reports the pain has been ongoing for the past 2 weeks. He has no prior medical conditions. The C-reactive protein level is elevated at 3.5 mg/dL (normal is less than 0.8 mg/dL), and hemogram and x-ray results are unremarkable. The ED physician treated Juan with ibuprofen and has referred him to your offce for follow-up.

Pattern Recognition

Approximately 10% of patient visits to family physicians are for musculoskeletal symptoms.4 The majority of these patients have relatively minor conditions such as sprains and strains; osteoarthritis; or localized inflammatory conditions, such as tendinitis or bursitis. However, some will have more serious conditions, including connective tissue diseases (CTDs).

Laboratory tests are useful in CTD diagnosis, but the process should start with a thorough history. Laboratory tests cannot substitute for the recognition of a pattern in the patient history by the physician. Many patterns are associated with CTDs and it can be useful to consider them in groups.

One group includes rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, Sjögren syndrome, and polymyositis. Each can occur as a seemingly isolated condition with its own classic presentation; they can also occur in overlapping patterns. Another group of conditions that shares patterns is the spondyloarthropathies, which include ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel-related arthritis. Polymyalgia rheumatica and giant cell (temporal) arteritis constitute another set of related conditions. However, the various vasculitis conditions seem to be unrelated—with the exception of Churg-Strauss syndrome, which might be a variant of polyarteritis nodosa altered by eosinophilia because of immunoglobulin (Ig) E-type allergic disease.

History

Emergency Conditions

Some nontraumatic musculoskeletal conditions constitute medical emergencies. For example, monoarthritis requires urgent evaluation and treatment, and should be considered septic arthritis until proven otherwise. Table 1 lists other musculoskeletal symptoms that require urgent evaluation, along with the major differential diagnoses and recommended initial evaluations.

Table 1

Symptoms and Conditions Requiring Urgent Evaluation

Symptom or Condition	Differential Diagnosis	Initial Evaluation
Monoarthritis	Infection, CTD, gout, pseudogout	Arthrocentesis, imaging studies, antibiotics
Fever, weight loss, fatigue	Infection, CTD, sepsis, acute malignancy	Directed culture testing, laboratory tests^a, imaging studies
Focal weakness	Entrapment, CTD, motor neuron disease	Laboratory tests^a, imaging studies
Diffuse weakness	Myositis, metabolic conditions, neoplasm, toxins	Laboratory tests^a
Numbness, paresthesias	Entrapment, inflammatory neuropathy, neoplasia, CTD	Laboratory tests^a, EMG, NCV
Claudication	Peripheral artery disease, vasculitis, cord compression	Laboratory tests^a, Doppler vascular studies, imaging studies

^aFor recommended laboratory tests, see Figure 1.

CTD = connective tissue disease; EMG = electromyogram; NCV = nerve conduction velocity.

Increased Morning Stiffness and Pain

Table 2 lists signs and symptoms that distinguish CTDs from osteoarthritis and local inflammatory conditions such as tendinitis. The key signs concern morning stiffness and whether pain decreases with activity.

Table 2

Signs and Symptoms Distinguishing Osteoarthritis and Local Inflammatory Conditions From CTD

Sign or Symptom	Osteoarthritis	Tendinitis/Bursitis	CTD
Morning stiffness	<1/2 hour	<1/2 hour	>1 hour
Discomfort	With activity	With activity	With inactivity or at night
Pain	Periarticular	Focal	Entire joint
Symmetry	Occasional	Uncommon	Common
Inflammation	Uncommon	Common	Common
Swelling	Bony	Soft	Soft
Extra-articular findings	None	None	Common

CTD = connective tissue disease.

Other Concerns

Information about illnesses of family members can indicate viral infection-related joint pain with symptoms that mimic those of a CTD. Hypersensitivity to drugs such as antibiotics and antidepressants can produce CTD-like syndromes (eg, serum sickness), resulting in an immune complex condition that manifests with arthritis. Proteins from nonhuman species, such as antitoxins and antivenins; hormones from nonhuman species; and streptokinase can also cause hypersensitivity.5

A review of systems can reveal constitutional symptoms, rash, sicca symptoms (eg, dry mouth, dry eyes), or symptoms involving multiple organs, any of which can indicate a CTD. Reports of pain all over the body along with a review of systems that shows no logical pattern point to a diagnosis of fibromyalgia.

Physical Examination

In patients with symptomatic joints, the physical examination should be focused on finding patterns

suggestive of osteoarthritis; localized inflammatory conditions, such as tendinitis or bursitis; or systemic disease (ie, CTD). The findings that distinguish these conditions are listed in Table 2. The presence of extra-articular findings, such as oral ulcerations, dry mucosa, rash, nodules, lymphadenopathy, pericardial or pleuritic rubs, organomegaly, or neurologic abnormalities increases the likelihood of a CTD.

Laboratory Tests

Figure 1 provides a general approach to patients presenting with polyarthralgias. Table 3 provides a list of the tests discussed in this section that are often used for evaluation of patients with suspected CTDs.

Figure 1

Initial Assessment of Patients With Polyarthralgias

ALP = alkaline phosphatase; ANA = antinuclear antibody; CBC = complete blood count; CRP = C-reactive protein; CTD = connective tissue disease; ESR = erythrocyte sedimentation rate; HBV = hepatitis B virus; HCV = hepatitis C virus; LFT = liver function test; OA = osteoarthritis; RF = rheumatoid factor; TSH = thyroid-stimulating hormone.

Table 3

Diagnostic Tests for CTD

Test	Assessment
Routine tests
Hemogram	Detect cytopenia
Liver function	Exclude hepatitis
Renal function	Assess renal function
Urinalysis	Detect proteinuria, cells, casts
Indicators of inflammation
C-reactive protein	Assess degree of inflammation
Erythrocyte sedimentation rate	Assess degree of inflammation
Specialized tests
Anticentromere antibodies	Limited scleroderma, CREST syndrome
Anticyclic citrullinated peptide antibodies	Rheumatoid arthritis
Anti-double-stranded DNA antibodies	SLE
Anti-Jo-1 antibodies	Polymyositis
Antimyeloperoxidase antibodies	Confirm positive ANCA in vasculitis conditions
ANCA	Wegener granulomatosis, vasculitis conditions
Antinuclear antibodies	SLE, scleroderma, Sjögren syndrome, polymyositis, dermatomyositis, mixed CTD
Antiphospholipid antibodies	Thrombotic syndromes, miscarriage
Antiproteinase 3 antibodies	Confirm positive ANCA test results in Wegener granulomatosis
Anti-RNP antibodies	Mixed CTD
Anti-Sm antibodies	SLE
Antitopoisomerase antibodies	Diffuse scleroderma
Complements C3 and C4	Lupus nephritis and others
Extractable nuclear antigen antibodies	Detect antibodies to antigens including SSA(Ro), SSB(La), RNP, Sm antigens
Rheumatoid factor	Rheumatoid arthritis
Anti-SSA(Ro) antibodies	Sjögren syndrome, SLE
Anti-SSB(La) antibodies	Sjögren syndrome, SLE

ANCA = antineutrophilic cytoplasmic antibody; CREST = calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasia; CTD = connective tissue disease; RNP = ribonucleoprotein; SLE = systemic lupus erythematosus; Sm = Smith; SSA(Ro) = Sjögren syndrome A; SSB(La) = Sjögren syndrome B.

Laboratory testing for CTDs should follow the history and physical examination if a pattern indicates that such a condition might be present. Arthritis panels should not be obtained because they increase the risk of false-positive results.

Few laboratory tests are highly sensitive and specific for CTD detection. The only highly sensitive tests are antinuclear antibody (ANA) tests, which are sensitive for SLE, and erythrocyte sedimentation rate, for which elevated levels are highly sensitive for polymyalgia rheumatica and temporal arteritis.6 The only highly specific tests are anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibody, which are specific for SLE, and antiproteinase 3, which is specific for Wegener granulomatosis.7 These tests are discussed in depth later in this section.

Routine Tests

Routine blood and urine tests should be obtained for any patient with suspected CTD. Hemogram will detect cytopenias, particularly lymphopenia, which are seen in SLE and related conditions. Urinalysis can reveal proteinuria in patients with CTD that affects the kidneys. Kidney and liver function also should be assessed. Abnormal liver function test results should prompt testing for antibodies to hepatitis B and C viruses.

Symptoms of these infections are similar to those of CTD.

Testing for thyroid disease, celiac disease, and vitamin D deficiency also should be considered. These conditions can manifest with symptoms similar to those of CTD. Laboratory testing in children should follow this approach;8 however, rheumatoid factor (RF) and ANA testing may have less clinical utility in children.9

Specific Tests

Erythrocyte Sedimentation Rate and C-Reactive Protein.

Fibrinogen is produced by the liver in response to inflammation and is thus called an acute phase reactant. Erythrocyte sedimentation rate (ESR) is an indirect measurement of fibrinogen, which is positively charged. Positively charged fibrinogen neutralizes the natural repelling negative charges on red blood cells, causing them to clump together and settle more quickly in a test tube.10 More fibrinogen causes faster settling and results in a higher ESR. Non-inflammatory ESR increases can also occur because of anemia, dyslipidemia, female sex, age, and pregnancy.

C-reactive protein (CRP) is also produced by the liver as an acute phase reactant. Obesity can increase CRP and ESR levels, but this increase might represent only the low-level inflammation associated with increased cardiac risk.11 The high-sensitivity CRP assay should not be used in patients with suspected inflammatory conditions because it is too sensitive. Small increases in CRP level measured with the high-sensitivity assay are more commonly associated with cardiac risk and less with CTD.

Virtually any inflammatory condition can slightly increase ESR and CRP levels (eg, ESR 25 to 50 mm/hour, CRP 1.0 to 3.0 mg/L). Moderate increases in ESR level (50 to 70 mm/hour) and CRP level (greater than 3.0 to 5.0 mg/L) can be due to viral, bacterial, or parasitic infection; myocardial infarction; surgery; or malignancies; as well as CTD. Table 4 lists common etiologies of an ESR 100 mm/hour or greater.6 Management of some inflammatory and infectious conditions can be monitored with serial measurements of ESR and/or CRP levels.

Table 4

Etiologies of Erythrocyte Sedimentation Rate of 100 mm/hour or Greater

Disease Category	Conditions
Connective tissue and rheumatic diseases	Acute gout Polymyalgia rheumatica/temporal arteritis Rheumatoid arthritis Systemic lupus erythematosus
Infectious diseases	Deep-tissue abscess Osteomyelitis Subacute bacterial endocarditis
Malignancies	Carcinoma Leukemia Lymphoma Multiple myeloma
Iatrogenic	Drug hypersensitivity

Information from Zacharski LR, Kyle RA. Significance of extreme elevation of erythrocyte sedimentation rate. JAMA. 1967;202(4):264-266.

Rheumatoid Factor.

RF is an antibody that binds to the constant chain of other antibodies. The IgM subtype of RF is typically chosen for measurement, but IgG, IgA, and IgE subtypes exist as well.

Rheumatoid factor is sensitive and somewhat specific for RA.12 A positive test result for RF is part of the diagnostic criteria for RA, but test results are only positive in 70% to 90% of patients with RA. RF is present less often in early disease. High titers of RF are associated with greater disease and extra-articular manifestations.

Rheumatoid factor can be found in CTDs that share the RA pattern, particularly Sjögren syndrome (RF is present in 70% of these patients), but also SLE, scleroderma, and polymyositis. It is not present with the seronegative spondyloarthropathies, gout, or pseudogout.12 Many other inflammatory states can also result in the presence of RF. These include some malignancies and chronic infections. Half of patients with bacterial endocarditis have positive RF test results.12 RF levels are not monitored in the treatment of CTDs.

Anticyclic Citrullinated Peptide Antibodies.

Anticyclic citrullinated peptide (anti-CCP) antibodies have similar sensitivity but higher specificity than RF in diagnosis of RA.13 Anti-CCP antibodies can be present early in the course of RA and can indicate more severe disease. They are particularly useful in the diagnosis of patients presenting with arthralgias resulting from conditions such as hepatitis C virus infection, in which RF is sometimes present. Such patients can have positive test results for RF but negative results for anti-CCP antibodies if RA is not present. Anti-CCP levels are not monitored serially in RA.

Newer methods for assessing antibodies directed toward other citrullinated peptides might provide improvements in sensitivity and specificity for diagnosis and prognosis in RA. Examples include assays involving fibrin/flaggrin citrullinated peptides, which might help identify more aggressive RA, and citrullinated vimentin, which might have greater sensitivity and specificity in the diagnosis of early RA.14,15

Complements.

Two components of the complement pathway, C3 and C4, have clinical utility in diagnosis and monitoring of SLE. Low levels of C3 or C4 are associated with SLE, particularly with lupus nephritis. If a level is found to rise and fall with disease severity, monitoring can help attribute new symptoms to SLE episodes. However, many patients have either normal or stable low levels of C3 and C4 that are unaffected by disease activity.16

Of note, any condition that produces immune complexes, including bacterial endocarditis and post-streptococcal nephritis, can bind and deplete serum complement levels. Therefore, low complement levels are not specific to SLE or any other CTD.

A recent study of pediatric patients with active and inactive SLE assessed the utility of measuring the q component of C1 (C1q) and antibodies to C1q.17 Patients with low levels of C1q and high levels of antibodies to C1q had greater disease activity. Also, high levels of antibodies to C1q were found to be predictive of kidney damage. The sensitivity of SLE diagnosis using antibodies to C1q was 96%, and the specificity was 98%. If these study results can be reproduced in other populations, these assays might be highly useful in SLE diagnosis and management.

Antinuclear Antibodies.

The presence of ANAs is central to diagnosis of CTDs through laboratory testing.18 Many referrals to rheumatology subspecialists are made on the basis of low-level positive ANA test results, with or without history or symptoms suggestive of CTD.

Typical results for ANA are negative at less than 1:40 serum dilution, indeterminate between 1:40 and 1:160, and clearly positive at serum dilutions 1:320 and greater.

The most effective method for ANA screening and determining titer involves incubating dilutions of patient serum with fluorescent-labeled probes on cultured cells, and then visualizing of the pattern of the various adherent ANA-antigen complexes. The patterns, their associated nuclear antigens, and the CTDs associated with those patterns and antigens are shown in Table 5.

Table 5

ANA Patterns and Associated Antigens and Conditions

Pattern	Antigen	Conditions
Homogeneous	DNA-protein complex	SLE
Diffuse	Histone	Drug-induced SLE
	Topoisomerase-1	Scleroderma
Speckled	RNP	Overlap/mixed syndromes
	Sm	SLE
	SSA(Ro)	Sjögren syndrome, SLE
	SSB(La)	Sjögren syndrome, SLE
	Other	Polymyositis/dermatomyositis Infection, malignancy
Nucleolar	RNA	Scleroderma
Peripheral	Double-stranded DNA	SLE
Centromeric	Centromere	Limited scleroderma, CREST syndrome

ANA = antinuclear antibody; CREST = calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasia; RNA = ribonucleic acid; RNP = ribonucleoprotein; SLE = systemic lupus erythematosus; Sm = Smith; SSA(Ro) = Sjögren syndrome A; SSB(La) = Sjögren syndrome B.

Information from Wiik AS, Fritzler MJ. Laboratory tests in rheumatic disorders. In: Hochberg MC, Silman AJ, Smolen JS, et al, eds. Rheumatology. 4th ed. Philadelphia: Mosby Elsevier; 2008:219-232.

Tests for antibodies against these various nuclear antigens—the so-called extractable nuclear antigens (ENAs)—can also be performed individually. After a patient has a positive ANA test result, the next step is to obtain these individual tests. Testing for antibodies against the individual antigens should be obtained for 2 reasons. First, one pattern on an ANA test result can predominate and obscure other patterns, thereby obscuring clues to the nature of the CTD present. Second, tests for antibodies against the individual antigens are far more specific than the patterns on ANA test results.

Some patients have negative ANA test results but symptoms highly suggestive of CTD. In this situation, testing for the individual antinuclear antigens should be guided by patient symptoms suggestive of a specific condition because such testing can often yield a false-positive result. One study of 8,470 samples sent to a referral laboratory showed that 9% of the samples with negative ANA test results (less than 1:40 serum dilution) had 1 or more positive test results on expanded testing to 1 or more of these other antigens.19 Such results indicate a possible diagnosis of CTD, despite a negative ANA test result.

Antibodies Against Individual Extractable Nuclear Antigens.

The antibodies against the individual ENAs for which follow-up antibody testing can be obtained include anti-dsDNA, anti-Sm antigen, anti-Sjögren syndrome A (SSA(Ro)), anti-Sjögren syndrome B (SSB(La)), antiribonucleoprotein (RNP), anticentromere, antitopoisomerase, and anti-Jo-1.

Anti-dsDNA antibodies are present in approximately 60% of patients with SLE, and occasionally in patients with other CTDs and in healthy patients. However, when present in patients with symptoms suggestive of SLE, they are considered highly specific for the disease.20

Patients with SLE can have levels of anti-dsDNA antibodies that correlate with disease activity, particularly with lupus nephritis. In such patients, this test can be helpful in monitoring disease progression and treatment response. Other assays have also been developed for this purpose, but a recent analysis that compared changes in anti-dsDNA levels with changes in other assay results (ie, antinucleosome and anti-actinin antibodies) showed no advantage over monitoring anti-dsDNA levels alone.21

Anti-Sm antibodies are present in approximately 40% of patients with SLE. But when present, anti-Sm antibodies are similar to anti-dsDNA antibodies in that they are highly specific for SLE.7,18 Anti-SSA(Ro) and anti-SSB(La) antibodies are associated with Sjögren syndrome. They are also present in patients with SLE. Anti-RNP antibodies are associated with overlap syndromes in 95% of patients, and particularly in those with high titers. The diagnosis of mixed CTD requires a positive RNP test result.

Anticentromere antibodies are present only in patients with limited scleroderma and in approximately 75% of patients with CREST (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, telangiectasia) syndrome.7,18 The CREST syndrome is discussed in more detail in Section Four.

Antitopoisomerase-1 antibodies, also called anti-Scl-70 antibodies, are present in approximately 40% of patients with the diffuse form of scleroderma.7,18 These antibodies have been associated with higher risk of pulmonary fibrosis. Anti-Jo-1 antibodies are present in approximately 30% of patients with polymyositis and are a marker for more severe disease.7,18

Antineutrophilic Cytoplasmic Antibodies.

Antineutrophilic cytoplasmic antibody (ANCA) testing is useful when patient symptoms are suggestive of Wegener granulomatosis or a vasculitis condition. There are 2 patterns of ANCA results reflecting the different binding of these autoantibodies to the cytoplasmic granules of neutrophils. One is the cytoplasmic, or C-ANCA, pattern, and the other is the perinuclear, or P-ANCA, pattern.

The C-ANCA test is most useful in the diagnosis of Wegener granulomatosis. Approximately 80% of patients with this condition have positive C-ANCA test results.7,18 These results should be confirmed by testing for antibodies to proteinease 3 (PR3) antigen. C-ANCA and PR3 antibody test results can be useful for monitoring treatment and recurrence.

The P-ANCA test is useful in the diagnosis of Churg-Strauss syndrome and other vasculitis conditions. A positive P-ANCA test result should be confirmed by testing for antibodies to the myeloperoxidase (MPO) antigen. Approximately 30% of patients with Churg-Strauss syndrome have positive test results for antibodies to P-ANCA and MPO.7,18

Antiphospholipid Antibodies.

Antiphospholipid antibody syndrome can manifest as venous or arterial thrombosis, cardiac valvular disease, multiple miscarriages, and/or a catastrophic antiphospholipid syndrome with multiple-organ failure.22 Patients with this syndrome have antiphospholipid antibodies, which include lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies. Any or all of these antiphospholipid antibody test results can be positive in these patients. False-positive rapid plasmin reagin test results for syphilis are common in patients with these antibodies.

Approximately 50% of patients with a lupus anticoagulant have SLE, and these antibodies cause thrombotic disease.22 However, a positive test result can be suggestive of a diagnosis of SLE even in the absence of thrombotic disease.

Ancillary Tests

Several other tests can be useful in the evaluation of patients with suspected CTDs. For example, in addition to excluding the possibility of septic arthritis, arthrocentesis for cell count and crystals can identify gout or pseudogout, both of which can have manifestations indistinguishable from those of RA.

X-rays can help evaluate patterns of erosive disease in joints. Subtle synovitis not found on physical examination can be detected by magnetic resonance imaging study or ultrasonography. Lung imaging with chest x-ray and high-resolution computed tomography scan can aid in the diagnosis of fibrotic lung disease, and magnetic resonance angiography can help diagnose vasculitis.

Electrocardiogram and echocardiogram can evaluate for cardiac abnormalities. Neurologic symptoms or muscle weakness might require electromyogram, nerve conduction studies, or nerve or muscle biopsies. Confirmation of a vasculitis condition, such as temporal arteritis, requires biopsy of involved tissue. Biopsy of a salivary lip gland in patients with sicca syndrome might show inflammation and help make the diagnosis of Sjögren syndrome. In lupus nephritis, staging and prognosis information are obtained by renal biopsy.

Case 1, cont’d. On physical examination of Juan, you find mild proximal muscle weakness. On further laboratory testing, the antinuclear antibody titer is positive (1:320 in a speckled pattern), and test results for rheumatoid factor and anticyclic citrullinated peptide antibodies are negative. The erythrocyte sedimentation rate is normal.

You refer Juan to a rheumatology subspecialist who confirms your findings. Further testing reveals positive results for anti-Jo-1 antibody and elevated creatine kinase and aldolase levels. Juan is then referred for an electromyogram, which confirms a diagnosis of polymyositis.

SECTION TWO

New Drugs

Case 1, cont’d. It is now 5 years later, and Juan, with a 5-year history of polymyositis, presents to your office for follow-up. He was originally treated with high doses of prednisone, with which he experienced resolution of joint pain and swelling and proximal muscle weakness. The creatine kinase (CK) and aldolase levels returned to normal.

After tapering the prednisone dosage, the symptoms returned along with an increase in the CK level, so Juan began taking long-term methotrexate. He recently discontinued use of the methotrexate because of elevated liver enzyme levels, and now takes low-dose prednisone.

At this visit, Juan says he has been seeing advertisements on the Internet for a new drug. He says he plans to see the rheumatology subspecialist next week, but asks your opinion about whether this new drug might be a treatment option for him because of its advertised lower risk of toxicity.

General Principles

Stepped Therapy

Management of connective tissue diseases (CTDs) should begin with educating patients about their disease and then address general self-care such as nutrition, exercise, and relaxation techniques. If treatment with drugs is needed urgently, it might be necessary to delay this basic counseling until patients are more comfortable and in stable condition. The most conservative medical treatments should be used first. Additional treatments should be added if the response to initial therapies is insufficient.

Drug Treatment to Confirm Diagnosis

Drug treatment can be used as a test of response, which in turn can aid in the diagnosis of CTD. For example, in polymyalgia rheumatica, an elderly patient with symptoms of axial pain, stiffness, or subjective weakness might experience complete symptom resolution within a few days of beginning daily therapy with 15 mg of prednisone, thus confirming the diagnosis. In contrast, in a patient with rheumatoid arthritis (RA), symptom resolution would typically take longer, perhaps 1 week or more.

Similarly, in a patient with suspected mild atypical systemic lupus erythematosus (SLE) in whom symptoms are not controlled with nonsteroidal anti-inflammatory drugs (NSAIDs), significant improvement after 3 months of hydroxychloroquine therapy would help confirm the diagnosis of SLE. Or, in the case of a patient with suspected spondyloarthropathy, a significant response to 3 months of high-dose indomethacin would confirm the diagnosis.

Adverse Effects

Family physicians are often the first to identify the adverse effects of drugs taken by patients with CTDs. Information about adverse effects, safety during pregnancy, and monitoring during use of these drugs is provided in Tables 6 and 7.

Complicated Regimens

Recent consensus recommendations for RA management published by the American College of Rheumatology noted there are more than 170 2- and 3-drug combinations used for RA management.23 This is also true for many other CTDs, which often makes the choice of therapy complicated.

Mild CTDs that can be managed with NSAIDs or a single course of steroids might not require consultation with a rheumatology subspecialist. However, unless a family physician has experience with and specific knowledge of a particular CTD, the decision to prescribe long-term drug therapy in addition to NSAIDs (especially therapy involving long-term steroid use or multidrug combinations) should be made in collaboration with a rheumatology subspecialist. Ongoing management and adverse effects should be comonitored by the family physician and the consulting rheumatology subspecialist.

Older Drugs

A variety of new drugs is available for CTD treatment. However, many of the older drugs still have a role in therapy and are first-line treatments for many patients.

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs can be used for treatment of any mild or nonspecific CTD. They are often used for pain control along with other drugs.

A recent meta-analysis estimated the relative risk (RR) of gastrointestinal bleeding or perforation with the use of NSAIDs.24 Overall, NSAID users had an average fourfold increased risk of gastrointestinal bleeding, but the RR varied considerably with different drugs: celecoxib (Celebrex) (RR=1.4), ibuprofen (RR=2.2), diclofenac (RR=3.6), meloxicam (RR=4.2), naproxen (RR=4.6), indomethacin (RR=5.1), ketoprofen (RR=5.1), piroxicam (RR=8.0), and ketorolac (RR=14.5). Indomethacin has been found to be slightly more effective, but it also is associated with greater risk.

With the exception of indomethacin, little overall difference in the effectiveness of various NSAIDs for CTD treatment has been shown. For most patients, a low-risk drug should be selected.

Steroids

Glucocorticoids are used for short-term and continuous management of almost all CTDs. In high doses, they are the mainstay for management of acute organ-threatening disease. Their associated risks are well known (Table 6).

Table 6

Adverse Effects and Pregnancy Recommendations for CTD Drug Treatment

Drug	Adverse Effects	Pregnancy Recommendation
Abatacept	Injection-site reaction, severe infections with increased risk of mortality	Avoid
Anti-interleukin-1	Injection-site reaction, neutropenia, severe infections with increased risk of mortality	Safe
Anti-interleukin-6	Hepatotoxicity, dyslipidemia, GI bleeding, myelosuppression^a, injection-site reaction, severe infections with increased risk of mortality	Avoid
Azathioprine	Myelosuppression^a, hepatotoxicity, cholestasis, pancreatitis	Safe
Cyclophosphamide	Myelosuppression^a, malignancy, hemorrhagic cystitis, infertility, alopecia	Teratogenic
Cyclosporine	Myelosuppression^a, hypertension, hepatotoxicity, renal toxicity, neuropathies, gout	Safe
Dapsone	Hemolytic anemia in G6PD deficiency, methemoglobinemia	Discontinue 4 weeks antepartum
Glucocorticoids	Hypertension, dyslipidemia, diabetes, cataracts, osteoporosis, osteonecrosis, infections, GI bleeding	Safe at lowest doses
Hydroxychloroquine	Retinopathy, GI symptoms, headache, myalgia, hemolytic anemia in G6PD deficiency, rash, sun sensitivity	Safe
Leflunomide	Diarrhea, GI symptoms, rash, hepatotoxicity, alopecia, rare myelosuppression^a	Teratogenic
Methotrexate	Mouth sores, GI symptoms, diarrhea, myelosuppression^a, alopecia, hepatitis/cirrhosis, pneumonitis	Teratogenic
Minocycline	GI symptoms, rash, sun sensitivity, hyperpigmentation of skin and/or gums	Avoid
Mycophenolate mofetil	Myelosuppression^a, GI symptoms, myalgia	Avoid
NSAIDs	GI symptoms, GI bleeding, hepatotoxicity, renal toxicity, hypertension, headache, aseptic meningitis	Discontinue in 3rd trimester
Rituximab	Injection-site reaction, severe infections with increased risk of mortality	Avoid
Statins	GI symptoms, myalgia, rhabdomyolysis	Avoid
Sulfasalazine	GI symptoms, rash, sun sensitivity, hemolytic anemia in G6PD deficiency, neutropenia	Safe
TNF inhibitors	Injection-site reaction, infusion reaction, activation of tuberculosis, fungal infections, opportunistic infections, severe infections with increased risk of mortality, rare demyelinating disease, lupus-like syndromes, exacerbation of heart failure	Safe

^aMyelosuppression includes increased risk of opportunistic infections.

CTD = connective tissue disease; G6PD = glucose-6-phosphate dehydrogenase; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs; TNF = tumor necrosis factor.

Information from Manzi S, Kao AH. Systemic lupus erythematosus: treatment and assessment. In: Klippel JH, Stone JH, Crofford LJ, et al. Primer on the Rheumatic Diseases. 13th ed. New York: Springer; 2008:327-338; Oliver AM, St Clair EW. Rheumatoid arthritis: treatment and assessment. In: Klippel JH, Stone JH, Crofford LJ, et al, eds. Primer on the Rheumatic Diseases. 13th ed. New York: Springer; 2008:133-141.

Table 7

Recommendations for Monitoring During CTD Drug Treatment

Drug	Baseline Tests	Routine Tests	Other Tests
Abatacept	CBC, Cr, LFT	–	–
Anti-interleukin-1	CBC, Cr, LFT, HBV, HCV^a, TST, chest x-ray	–	–
Anti-interleukin-6	CBC, Cr, LFT, HBV, HCV^a, TST, chest x-ray	CBC, LFT monthly; lipid profile bimonthly after initiation, then every 6 months	–
Azathioprine	CBC, Cr, LFT, HBV, HCV^a, bilirubin, amylase	CBC, Cr, LFT every 3 months	Every 2 weeks with dosage change
Cyclophosphamide	CBC, Cr, LFT, HBV, HCV^a	CBC, Cr, LFT, UA monthly	Every 2 weeks with monthly IV dose or with dosage change
Cyclosporine	CBC, Cr, LFT, UA, HBV, HCV^a, lipid profile, uric acid	CBC, Cr, LFT, UA, uric acid every 2 months	Every 2 weeks with dosage change
Dapsone	CBC, Cr, LFT, G6PD^b	CBC, LFT every 3 months	Every 2 weeks with dosage change
Glucocorticoids	BG, lipid profile, BP, DXA	BP, BG every 6 months	HbA1c, lipid profile annually, DXA every 6 months
Hydroxychloroquine	Eye examination^c, G6PD^b	Eye examination^c annually	–
Leflunomide	CBC, Cr, LFT, HBV, HCV^a	CBC, Cr, LFT every 3 months	Every 2 weeks with dosage change
Methotrexate	CBC, Cr, LFT, albumin, HBV, HCV^a	CBC, Cr, LFT, albumin every 2 months	Every 2 weeks with dosage change
Minocycline	CBC, Cr, LFT	Cr, LFT every 6 months	ANA for lupus-like symptoms
Mycophenolate	CBC, Cr, LFT, HBV, HCV^a	CBC, Cr, LFT every 2 months	Every 2 weeks with dosage change
NSAIDs	CBC, Cr, LFT, UA, BP	Cr, LFT, BP every 6 months	CBC annually
Rituximab	CBC, Cr, LFT, HBV, HCV^a, TST, chest x-ray	CBC every 3 months	–
Statins	LFT, CK, lipid profile	LFT every 6 months	CK with pain or weakness
Sulfasalazine	CBC, Cr, LFT, G6PD^b	CBC, LFT every 3 months	–
TNF inhibitors	CBC, Cr, LFT, HBV, HCV^a, TST, chest x-ray	CBC every 3 months	–

^aIf serology test result for HCV is positive, assess quantitative virus RNA level.

^bScreening for G6PD deficiency is only needed in high-risk groups (eg, individuals of African, Middle Eastern, or South Asian descent).

^cEye examination includes retinal examination and visual fields.

ANA = antinuclear antibody; BG = blood glucose; BP = blood pressure; CBC = complete blood count; CK = creatine kinase; Cr = creatinine; CTD = connective tissue disease; DXA = dual-energy x-ray absorptiometry; G6PD = glucose-6-phosphate dehydrogenase; HbA1c = glycated hemoglobin; HBV = hepatitis B virus; HCV = hepatitis C virus; IV = intravenous; LFT = liver function test; NSAID = nonsteroidal anti-inflammatory drug; TNF = tumor necrosis factor; TST = tuberculin skin test; UA = urinalysis.

Information from Manzi S, Kao AH. Systemic lupus erythematosus: treatment and assessment. In: Klippel JH, Stone JH, Crofford LJ, et al, eds. Primer on the Rheumatic Diseases. 13th ed. New York: Springer; 2008:327-338; Oliver AM, St Clair EW. Rheumatoid arthritis: treatment and assessment. In: Klippel JH, Stone JH, Crofford LJ, et al, eds. Primer on the Rheumatic Diseases. 13th ed. New York: Springer; 2008:133-141.

All patients taking steroids in dosages greater than the equivalent of 7.5 mg of prednisone for more than 6 months should undergo bone density measurement and begin preventive therapies, including calcium and vitamin D supplementation.25 Further therapies should be added as indicated, based on bone density measurements. Patients taking long-term steroids can develop acute Addisonian-like crisis after abrupt withdrawal. In patients with psoriatic arthritis, the withdrawal of steroids can lead to intense exacerbations of skin disease.

Hydroxychloroquine, Sulfasalazine, and Minocycline

Hydroxychloroquine is the first-line treatment for SLE if serious or life-threatening complications are absent.26 It also can be used in any patient with CTD without signs of progressive organ damage. Sulfasalazine and minocycline should be avoided in SLE, Sjögren syndrome, and scleroderma, but they can be used to treat mild nonerosive RA and the spondyloarthropathies. There are overall low risks of adverse effects with these drugs.

Minocycline is used for its immunomodulatory activity and not for its activity against any causative organisms, such as Chlamydia. However, in a recent study of chronic Chlamydia-induced reactive arthritis that tested a combination of antibiotics, 17 of 27 (63%) of minocycline-treated patients experienced good outcomes, compared with 3 of 15 (20%) of patients taking placebo.27 Symptoms completely resolved in 6 of 27 (22%) minocycline-treated patients and none treated with placebo. Reproduction of this outcome might allow for reconsideration of routine treatment for spondyloarthropathies, at least for patients with detectable persistent Chlamydia antigens.

Dapsone

Dapsone is used to treat dermatitis herpetiformis, and for various off-label indications, including inflammatory bowel disease and CTDs, usually in cases in which other drugs have been ineffective. Its use is limited by adverse effects, including a rare but life-threatening hypersensitivity syndrome, agranulocytosis, and methemoglobinemia.28

Methotrexate

Methotrexate was the gold standard for RA treatment until approval of the tumor necrosis factor (TNF) inhibitors.29 Methotrexate is still widely used for RA treatment. It has also been used in the management of many other inflammatory CTDs, albeit with various degrees of effectiveness.

Methotrexate should not be used in patients with renal insufficiency. Alcohol use should be limited to 1 drink/week because of the increased risk of hepatotoxicity. Complete blood count, liver function tests, and creatinine level should be obtained every 2 months, and every 2 weeks with dosage changes.

Oral methotrexate should be administered once weekly, usually starting at 15 mg, and should be taken with folic acid 1 mg/day to minimize adverse effects.29 If this is ineffective, the dosage can be increased to 20 mg after 3 months. Dosages up to 25 mg can be used; subcutaneous administration might prevent gastrointestinal absorption difficulties.

If a warning appears on an electronic ordering system or a pharmacist contacts the office regarding the interaction of methotrexate and NSAIDs, disregard this warning. It only pertains to high dosages of methotrexate administered for chemotherapy, not for the dosages for RA treatment.

When methotrexate alone has been ineffective, a 3-drug combination has been used for RA treatment, with sulfasalazine and hydroxychloroquine added to methotrexate. A recent study showed that adding a TNF inhibitor to methotrexate was more effective than the 3-drug combination.30

Leflunomide and Azathioprine

Leflunomide, a pyrimidine-synthesis inhibitor, is often used in RA treatment when methotrexate is ineffective or adverse effects occur. It can be added to methotrexate with a slight additional risk of adverse effects. Azathioprine, a purine-synthesis inhibitor, has similar effectiveness in CTDs but is not as well tolerated over time.

Cyclophosphamide

Cyclophosphamide, an alkylating agent, has long been considered the most effective drug in the treatment of life-threatening CTDs. It is also a standard treatment for Wegener granulomatosis and most forms of severe vasculitis.31

Cyclophosphamide is associated with high risks of infection and malignancy, as well as risks of irreversible infertility and hemorrhagic cystitis. The trend has been toward monthly intravenous therapy to decrease overall toxicity, with the largest decrease seen in the incidence of hemorrhagic cystitis.

More recently, biologic drugs are being used for last-resort treatment in patients with many rheumatologic conditions. Overall, they are associated with less toxicity than cyclophosphamide.

Newer Drugs

Mycophenolate and Cyclosporine

The immunosuppressive drugs mycophenolate mofetil and cyclosporine are similarly effective in managing a wide range of CTDs. However, cyclosporine has many adverse effects that limit its routine use.

Mycophenolate has been particularly effective in SLE treatment, and its use in CTD management is increasing. One study showed significant benefits of

mycophenolate in the treatment of 6 of 7 patients with polymyositis after ineffective use of methotrexate and other immunosuppressive drugs.32

Biologic Therapies

The biologic drugs are monoclonal antibodies directed against cytokines and immune-cell surface receptors. They can act to block or deplete cytokines, block receptors, or selectively deplete immune cell subtypes. Tables 6 and 7 list adverse effects associated with these drugs and recommendations for the monitoring of patients taking them.

A biologic drug is typically administered as combination therapy with a nonbiologic immunosuppressive drug, such as methotrexate. The combination acts synergistically, with the immunosuppressive drug acting to decrease development of antibodies that can neutralize the biologic. No 2 biologic drugs are administered together because of the high risk of adverse effects.23 Overall, there does not seem to be an increased risk of malignancies over the baseline increased risk present in patients with CTDs.33

Indications.

Most of the TNF inhibitors are approved by the Food and Drug Administration (FDA) for treatment of RA, the spondyloarthropathies, and juvenile arthritis. Abatacept (Orencia) is approved for RA, juvenile RA, and juvenile idiopathic arthritis. Tocilizumab (Actemra) is approved for RA only. Rituximab (Rituxan) is approved for treatment of RA and several hematologic malignancies.

The TNF inhibitors are typically used after 1 or more nonbiologic drugs are ineffective.34 The other biologic drugs are typically used after 1 or more TNF inhibitors are ineffective.

Often these drugs are used off-label to treat life-threatening or refractory CTDs. For example, both TNF inhibitors and rituximab have been used effectively in several small studies of therapy for refractory polymyositis.35,36 Rituximab also has been used for SLE and lupus nephritis treatment.37,38

These drugs are by far the most expensive used in CTD treatment. However, there are significantly more complete remissions of disease in RA with the addition of a biologic drug to methotrexate therapy than with methotrexate alone.30 Even without complete remission, there are significant improvements in almost all patients. One study that assessed loss of productivity due to RA showed the addition of etanercept (Enbrel) to methotrexate reduced by 50% the number of days of work lost because of disease compared with methotrexate alone.39

Treatment Regimens.

Most of the TNF inhibitors can be administered subcutaneously at home by the patient every 1 to 4 weeks, with the exception of infliximab (Remicade). Infliximab and most of the other biologic drugs should be administered by intravenous infusion every 1 to 2 months.30 Rituximab is usually administered as 2 intravenous infusions, 2 weeks apart, every 6 months.

Theoretical concerns exist about using any drug that is administered every 6 months because the effects of immunosuppression will not quickly subside after discontinuing the drug. In practice, this has not been an issue. TNF inhibitors should be discontinued at least 1 week before surgery.

Anakinra (Kineret) should be administered subcutaneously daily.40 It is associated with a high rate of injection-site reactions (70%) and is less effective for RA treatment compared with other biologic drugs. Overall, more effective choices exist for biologic therapy.

Integrative Medicine Therapies

Several dietary supplements and herbal therapies have shown some effectiveness in CTD treatment. In 1 randomized placebo-controlled trial in patients with SLE, treatment with omega-3 polyunsaturated fatty acids had a beneficial effect on disease activity. 41 Treatment with 3 g/day showed benefit in reducing SLE symptoms on standard measures and improving lipid profile results.

Another study showed that an oral creatine supplement, along with exercise, appeared to act synergistically with immunosuppressive treatment to increase muscle strength in patients with polymyositis, compared with exercise alone.42 Topical vitamin E gel was shown to improve healing of digital ulcers in scleroderma.43

In 1 study, a Chinese herbal treatment with Tripterygium wilfordii, also known as thunder god vine, was compared with sulfasalazine in patients with RA.44 This treatment was shown to be more effective than sulfasalazine. However, the study was limited by a large number of patients in both groups who discontinued treatment due to ineffectiveness or adverse effects.

In general, herbal preparations and supplements such as Echinacea and alfalfa (Medicago sativa) that are thought to increase immune activity should be avoided in patients with CTDs. Such substances could theoretically promote autoimmune mechanisms rather than inhibit them.

Drug Treatments Under Investigation

Research is ongoing into more effective treatments for patients with CTDs. The US government clinical trials registry currently lists approximately 250 clinical trials for lupus, and more than 100 for scleroderma.45,46

One new experimental drug, aminaftone, which has been studied in the treatment of venous capillary conditions, has also been studied in patients with scleroderma. It has action that is promising for treatment of scleroderma-associated vascular complications.47 This nonbiologic drug might be useful if it can be used synergistically with biologic drugs.

Statins have shown anti-inflammatory effects in RA management. Their anti-inflammatory action in other CTDs is unclear. For example, a recent small 3-month study in patients with SLE showed beneficial effects of statin treatment in lowering lipid levels, but few effects on SLE activity or inflammatory markers.48

A new microemulsion formulation of nitroglycerin shows promise in the treatment of Raynaud phenomenon.49 A randomized controlled trial found the formulation was effective and associated with no more headache, dizziness, or skin irritation than placebo.

Immunologic surgery may be the long-term future of CTD treatment. In this approach, selective immune responses to antigens known to be etiologic in CTDs would be targeted for down-regulation, perhaps using the endogenous T-cell suppressor system.50 This treatment has not yet reached the stage of testing in humans.

Case 1, cont’d. You and Juan review the drug treatment options currently available. Rituximab is an acceptable choice but is very expensive and would likely be rejected by the health insurance company. Azathioprine is an older drug that has been used effectively in polymyositis, but often it is not as well tolerated long-term as is mycophenolate mofetil. Intravenous immunoglobulin has also been used in some refractory cases. You decide to make a decision in collaboration with the rheumatology subspecialist.

SECTION THREE

Systemic Lupus Erythematosus

Case 2. Erica, a previously healthy 30-year-old black woman, presents to your office reporting fatigue and joint pain for 1 month. She also reports loss of appetite because of painful mouth ulcers, painful anterior neck swelling, and a 2.3-kg (5-lb) weight loss during the same period. The temperature is 38.1°C (100.1°F). Physical examination reveals 3-mm erythematous ulcerations of the hard palate and 5-mm gray buccal ulcerations. Also present are mild but painful anterior cervical adenopathy, and pain and swelling of the left wrist and proximal interphalangeal joint of the right index finger. Erica is worried about what has caused this condition and how long it will affect her.

Clinical Findings and Diagnostic Criteria

Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease with multifaceted manifestations. It is characterized by autoantibody responses to nuclear antigens. The disease often involves the skin, joints, kidneys, blood cells, and nervous system but almost any organ can be affected.

In women, SLE usually manifests during childbearing years and can have adverse effects on fertility and fetal health. Because the disease starts early, lasts the life span, and typically requires management with drugs, consideration must be given to the long-term adverse effects of the disease and the drugs. In particular, increased risks of atherosclerosis and osteoporosis should be addressed early in the disease course.

The formal diagnosis of SLE requires the presence of 4 of 11 criteria (Table 8).51,52

Table 8

Revised Criteria for SLE Diagnosis

SLE can be diagnosed if 4 or more of the 11 criteria are present, either serially or simultaneously.
Malar rash	Fixed erythema, flat or raised, sparing the nasolabial folds
Discoid rash	Erythematous raised, scaling or follicular plugging, scarring
Photosensitivity	Rash due to sunlight, by history or observed
Oral ulcers	Oral or nasopharyngeal, usually painless
Arthritis	Nonerosive, 2 or more joints, tenderness, swelling, effusion
Serositis	Pleuritis: pain, rub, or effusion Pericarditis: on electrocardiogram, rub, or effusion
Renal condition	>0.5 g/day proteinuria or >3+ dipstick proteinuria or cellular casts
Neurologic condition	Seizures or psychosis (without other cause)
Hematologic condition	Hemolytic anemia or leukopenia (<4,000/mcL) or lymphopenia (<1,500/mcL) or thrombocytopenia (<100,000 mcL)
Immunologic condition	Antibody to native (double-stranded) DNA or antibody to Smith antigen or abnormal level of anticardiolipin antibodies, lupus anticoagulant positive test result, or false-positive serologic test result for syphilis
Positive antinuclear antibody test result

SLE = systemic lupus erythematosus.

Adapted from Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271-1277; information from Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.

Differential Diagnoses and Subtypes

Systemic lupus erythematosus is characterized by extremely pleomorphic manifestations. It can include mild symptoms, usually fatigue, arthralgias, and myalgias. In patients with no or mild rash, SLE can be misidentified as fibromyalgia or chronic fatigue syndrome. A trial of low-dose corticosteroids or hydroxychloroquine might assist in differentiation, although it is important to remember the high rate of placebo response among patients with fibromyalgia and chronic fatigue syndrome.

Symptoms of thyroid disease are similar to those of SLE. Both conditions are associated with similarly patterned high titers of antinuclear antibodies. This is particularly true with Graves disease and Hashimoto disease (ie, autoimmune thyroiditis).

Three patterns of SLE disease activity have been identified: chronic-active, relapsing-remitting, and long-quiescent.53 The chronic-active pattern is defined as disease activity for at least 1 year. The relapsing-remitting pattern consists of periods of disease activity with at least 2 medical visits 3 months apart, with inactivity during those 3 months. The long-quiescent pattern is defined as no activity in a 1-year period.

In the study that defined these patterns, 200 patients were monitored for up to 7.5 years. The chronic-active pattern was most common (58%), the relapsing-remitting pattern was intermediately common (26%), and the long-quiescent pattern was the least common (16%). Several patients exhibited multiple patterns, including some patients with all 3 patterns over time.

With severe disease, any organ can be affected. Excessive sun exposure has been shown to trigger systemic illness with rapid progression to multiorgan failure. Sepsis and acute leukemia must be ruled out in the evaluation of patients with severe SLE.

Epidemiology, Etiology, and Mortality

Systemic lupus erythematosus is more common in young women, with a female-male incidence ratio of approximately 9:1, and typically develops between ages 15 and 40 years.54 However, SLE can develop at almost any age, and the female-male incidence ratio decreases to approximately 2:1 with development before puberty and at older ages.

The overall prevalence of SLE is approximately 0.1% of the US population (ie, 1 case per 1,000 individuals).54 The disease has a greater prevalence and is more severe among blacks and Hispanics.

Multiple factors are associated with development of SLE.55 Genetic factors include HLA-DR2 and HLA-DR3, certain immunoglobulin and T-cell subtypes, cytokines, multiple immunoregulatory genes, complement genes, and hormones.

Environmental factors associated with SLE include ultraviolet light exposure; responses to microbial infections, drugs, and toxins (including inhaled crystalline silica); various solvents and pesticides; cigarette smoking; and use of hair dye.56 Epstein-Barr virus is thought to be linked to SLE, perhaps through direct stimulation of B cells.57

Drugs known to induce SLE include procainamide and hydralazine, which are now less commonly used, and isoniazid. Sulfonamide antibiotics, including trimethoprim-sulfamethoxazole, are associated with SLE exacerbations and should be avoided in patients with SLE.58 The newer tumor necrosis factor (TNF) inhibitors are associated with elevated levels of autoantibodies as well as confirmed cases of SLE.

The interaction of these multiple factors leads to chronic inflammation in a variety of organs. However, the precise role of autoantibodies in directly causing pathology is not clear.

The role of autoantibodies in directly mediating disease is clearest in lupus nephritis, but the inability to properly regulate immune responses appears to be significant in the overall etiology and pathogenesis of SLE. This is best illustrated by the failure of apoptosis, programmed self-destruction of immune cells, leading to antibody- and cellular-mediated autoimmune responses.59

The mortality rate from SLE in the 1950s was estimated at 50% at 5 years.60 Today, the survival rates are estimated to be approximately 96% at 5 years after diagnosis, 93% at 10 years, and 78% at 15 to 20 years. The survival rates are similar for patients with mild disease and those with severe disease for the first 10 years, after which the survival rate decreases for those with more severe disease. Higher mortality rates are found among males, blacks, and Hispanics.

The major cause of mortality in SLE is currently premature atherosclerosis, with an estimated 50-fold increased risk of myocardial infarction.61 Thus a patient with lupus, often a young adult woman who presents with chest pain, should be evaluated for acute

myocardial infarction despite lack of other traditional cardiovascular risk factors.

Older studies showed the leading cause of mortality was previously infection, presumed secondary to the immune deficiency of SLE itself in combination with immunosuppressive drugs. There may also be an increased risk of malignancy in SLE that is unassociated with drugs.62

Diagnosis

Systemic lupus erythematosus is diagnosed clinically because no single laboratory test exists that can confirm the diagnosis. The diagnostic criteria in Table 8—a mix of clinical and laboratory findings—provide an outline.52 Constitutional symptoms can be present, with symptoms of fever, lymphadenopathy, and weight loss. Infection should be ruled out before attributing these symptoms to SLE.

Mucocutaneous Lesions

Mucocutaneous symptoms are common, with most rashes involving sun-exposed skin. Recurrent urticaria can be a manifestation of SLE. Painless erythematous ulcerations of the hard and soft palate can be present, and painful oral lesions tend to occur on the buccal mucosa. Dry eyes and mouth (ie, sicca syndrome) are common. Sjögren syndrome is less common.

Joints

Systemic lupus erythematosus causes arthralgias and synovitis, but with erosive joint disease, an overlap syndrome with rheumatoid arthritis (RA) should be considered. Tendon and joint laxity can occur and Jaccoud arthritis (ie, ulnar deviation of the second to fifth fingers and subluxation of the metacarpophalangeal joints) can resemble the ulnar deviation of RA, but it differs in that in SLE the digits are easily reducible.

Symptomatic serositis typically manifests as chest pain from pleuritis or pericarditis, or both. Effusions might not be present. Serositis can occasionally manifest as the sole symptom of SLE.

Renal and Hepatic Conditions

Renal conditions cause significant morbidity and mortality in patients with SLE, and are more common in blacks than whites.60 Hematuria and red or white blood cell casts may indicate nephritis. Renal biopsy identifies 5 types of nephritis: mild mesangial, mesangial, focal, diffuse, and membranous. The most severe type, diffuse proliferative glomerulonephritis, can rapidly lead to renal failure.

Autoimmune hepatitis is uncommon in patients with SLE. Mild abnormalities in liver function test results are common and typically resolve with treatment.

Neuropsychiatric Conditions

Multiple neuropsychiatric conditions can occur in patients with SLE. The most common is cognitive impairment, which occurs in 80% of patients by 10 years after diagnosis.63 Other neurologic manifestations include seizures, psychosis, cranial neuropathy, transverse myelitis, peripheral neuropathy, mononeuritis multiplex, and encephalopathy. An increased risk of aseptic meningitis is associated with use of sulfonamide antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs).

Cytopenias

Cytopenias are common. The presence of lymphopenia is helpful in confirming an SLE diagnosis because it is otherwise uncommon in the general population. Thrombocytopenia can be severe and resistant to therapy. Patients with thrombocytopenia do not respond as well to splenectomy compared with splenectomy in the treatment of patients with idiopathic thrombocytopenia.64

Autoantibodies

Autoantibodies are the hallmark sign of SLE and a variety of them are seen. Loose associations have been found between the various autoantibodies and SLE symptoms. As previously discussed, the presence of anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies is highly specific for SLE, though these are not present in all cases. In certain patients, the anti-dsDNA levels can correlate with disease activity.

Complement levels, particularly C3 and C4, can be used to monitor disease activity. However, treatment should be based on signs and symptoms of disease. For example, in a patient with anti-dsDNA and anti-Sm antibodies and/or low complement levels but no symptoms, no treatment is needed. (An annual urinalysis should be performed to rule out asymptomatic nephritis in such patients.)

In a study of 157 patients with SLE, measurement of levels of erythrocyte-bound C3d and C4d and proteolytic fragments of C3 and C4 provided significantly more information about disease activity compared with assays of serum C3 and C4 levels.65 Newer assays may replace or supplement older assays as they become more widely available and are shown to be useful in evaluation.

Anti-SSA(Ro) and anti-SSB(La) antibodies can be markers for Sjögren syndrome, but are also markers for increased risk of cardiovascular abnormalities in infants born to women with SLE. The presence of antihistone antibodies can be helpful in the diagnosis of drug-induced SLE. Antiphospholipid antibodies, including anti-beta-2-glycoprotein I, are present in approximately 50% of patients with SLE and can be associated with thrombosis, thrombocytopenia, and miscarriage.22 However, these patients are usually asymptomatic.

In some patients with SLE, the erythrocyte sedimentation rate and C-reactive protein (CRP) level can be used to monitor disease activity. In other patients with SLE, these parameters remain within normal ranges even with severe disease.

Atherosclerosis

Because of the role of atherosclerotic cardiovascular disease (CVD) in SLE-related morbidity and mortality, routine tests for older and newer biologic markers for increased atherosclerotic risk should be obtained.66 Older markers include lipid, homocysteine, and CRP levels. Newer markers include dysfunctional proinflammatory high-density lipoprotein (HDL), anticardiolipin antibody beta-2-glycoprotein I, and antibodies to apolipoprotein A-I and HDL.67,68,69 Antibodies to apolipoprotein A-I and HDL seem to be general markers of disease activity and correlate with anti-dsDNA antibodies in lupus nephritis.

Treatment

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs are often used early in SLE treatment and can be effective for arthralgias and mild serositis. They should be avoided in patients with lupus nephritis and renal insufficiency. NSAIDs can also precipitate aseptic meningitis.

The cyclooxygenase-2 inhibitors may have some gastroprotective effects but should be avoided in patients with increased risk of CVD. NSAIDs must be discontinued in the third trimester of pregnancy to prevent risk of premature closure of the ductus arteriosus.

Steroids

Corticosteroids are effective in management of many acute inflammatory SLE symptoms. Low dosages (ie, prednisone 5 mg/day) can be used with or without other drugs for treatment of mild SLE. Higher dosages can be used intermittently for moderate to severe disease episodes. Steroids can be given as a bridge until the slow-acting drugs start to become effective.

Topical steroids can be used for skin symptoms. Intra-articular steroids can be useful for managing inflammation of isolated joints. However, in the case of monoarthritis, infection must be excluded before steroid injection is performed.

Hydroxychloroquine

All patients with SLE should be treated with hydroxychloroquine unless intolerant.70 High-quality long-term data show synergy between hydroxychloroquine and other drugs. Hydroxychloroquine therapy has been found to prevent disease episodes and reduce need for steroids.71 It also helps prevent CVD and thrombosis. Therapy with hydroxychloroquine is associated with higher survival rates.72

Hydroxychloroquine therapy requires 6 weeks to 3 months to show benefit. It can be combined with NSAIDs for treatment of mild SLE symptoms, such as cutaneous manifestations and arthralgia.

Immunomodulatory Drugs

Several steroid-sparing immunomodulatory drugs commonly used to manage RA have all been used off-label for SLE treatment. They include azathioprine, methotrexate, leflunomide, and cyclophosphamide. Cyclosporine should be avoided in patients with SLE because of the adverse effect of hypertension.

One 12-month double-blind randomized study of 86 patients with active SLE evaluated the effectiveness

of methotrexate.73 No patients were taking immunosuppressive drugs at baseline and approximately 50% were taking steroids. Minor decreases in SLE activity were found on standard measures, but the mean dosage of steroids was lowered significantly in the group receiving methotrexate.

The study was complicated by a larger percentage (91%) of patients in the placebo group taking hydroxychloroquine compared with 66% in the methotrexate group. Approximately 30% of patients discontinued study participation because of SLE episodes. Patients in the methotrexate group experienced a higher rate of gastrointestinal adverse effects. Overall, methotrexate was found to be beneficial. However, a drug such as mycophenolate mofetil might be a more effective choice of steroid-sparing drug after ineffectiveness of hydroxychloroquine.

Cyclophosphamide has been the gold standard for lupus nephritis treatment since the 1960s. Intravenous monthly pulse therapy has been used, and is associated with less bladder toxicity compared with oral daily dosages. Adverse effects include nausea, alopecia, bone marrow suppression, infections, and ovarian failure. The risk of the latter can be decreased with use of leuprolide.74

In the past 5 years, induction and maintenance treatment with mycophenolate mofetil has emerged as an often-preferred treatment for lupus nephritis, and cyclophosphamide is less often used. Overall, there is less toxicity associated with mycophenolate, gonadal function is preserved, and it may be more effective than cyclophosphamide for blacks.75

Rescue Treatments

Severe SLE that affects the central nervous system, heart, kidneys, blood cells, and skin can be resistant to high-dose glucocorticoids and most of the drugs discussed in this section. For such patients, rescue methods have been used that include plasmapheresis, intravenous immunoglobulin administration, and

stem cell transplantation. A host of new biologic drugs is emerging that may be useful and will likely decrease the need for these rescue therapies.

Biologic Drugs

The TNF inhibitors have revolutionized treatment of RA. However, their use has been somewhat avoided in SLE because these drugs often increase autoantibody production and have been associated with rare risks of symptomatic autoimmune and lupus-like syndromes.

Nonetheless, the TNF cytokine has been implicated in SLE pathogenesis, including in lupus nephritis, and the use of biologic drugs is under investigation. One small 24-week study assessed the safety of infliximab in 27 patients with active SLE.37 Nine patients were treated with infliximab, the other 18 were assigned to the control group. Four patients in the treatment group discontinued participation due to infliximab-related adverse effects. In the 5 remaining patients, several measures of active SLE improved, including nervous system, renal, mucocutaneous, and hematologic markers. Larger studies might more accurately identify patients who might respond to TNF inhibitor therapy without significant adverse effects.

B-cell depletion biologic drugs are also being studied for SLE treatment—with mixed results. One open-label study using rituximab as rescue therapy for patients with active SLE unresponsive to standard immunosuppressant therapy showed beneficial results.76 However, results of a placebo-controlled study did not show an overall significant response.77

The B-cell survival factors B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are other targets in SLE treatment. Belimumab is a monoclonal antibody to BLyS recently approved by the Food and Drug Administration for treatment of SLE.

One placebo-controlled trial of belimumab enrolled 449 patients with active SLE.78 With approximately 110 subjects in each group, the trial did not show significant benefits for the primary end points, but twice as many patients in the treatment group were able to reduce their steroid dosages. The treatment was not found to be associated with major adverse effects. Atacicept, another agent that targets B-cell survival factors, showed significant biologic activity with decreases in B cells and immunoglobulins in an early trial.79

Approach to Drug Therapy

Many new drugs are now available for SLE treatment. They are often used in combination, and this leads to complicated treatment regimens that require careful patient monitoring. Except for the mildest cases of SLE that are effectively treated with NSAIDs alone, a rheumatology subspecialist should be consulted to aid in diagnosis, guide treatment, and help monitor for adverse effects.

Case 2, cont’d. Systemic lupus erythematosus (SLE) is a possible diagnosis for Erica, though infectious and neoplastic conditions should also be considered. After evaluating the symptoms, you decide to proceed with initial laboratory testing for SLE. You obtain tests for antinuclear antibody (ANA), hemogram with differential with platelets, serum creatinine, thyroid-stimulating hormone, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and urinalysis. These test results point to a diagnosis of SLE.

You counsel Erica that SLE is a lifelong disease, and she will need long-term treatment and monitoring for possible progressive organ damage. You advise avoidance of strong sunlight. You also discuss the risks of pregnancy.

After this discussion, you initiate treatment with prednisone. Erica is started on 30 mg for 2 days with directions to decrease the dosage by 5 mg every 2 days, and then continue at a dosage of 5 mg/day.

On return to your office the next week, Erica says she felt significantly better after 48 hours of treatment. Laboratory test results show a high titer of ANA (1:640 in a homogeneous pattern), slight anemia with a hematocrit level of 10.5 g/dL; and normal platelets and white blood cell count. The ESR and CRP level are slightly elevated at 32 mm/hour and 2 mg/L, respectively. The rest of the test results are normal or negative.

After the diagnosis of SLE is confirmed, Erica is started on hydroxychloroquine. You taper the prednisone dosage by 1 mg/month after Erica has been taking hydroxychloroquine for 1 to 2 months. You make a note to annually monitor retinal changes, measure the creatinine level, and obtain a hemogram and urinalysis.

SECTION FOUR

Scleroderma

Case 3. Alex, a 45-year-old white man, presents to your office reporting pain and stiffness in the joints for the past 6 weeks. He says his fingers blanch in the cold and then turn blue. He also describes fatigue, myalgias, exertional dyspnea, and a nonproductive cough. The physical examination is notable for fine inspiratory crackles at both lung bases. Telangiectasias and thickening of the skin of the hands and face are present. In addition, there is a small ulcer on the extensor surface of the left third finger.

Clinical Findings and Diagnostic Criteria

Scleroderma, also known as systemic sclerosis, is a chronic condition characterized by fibrosis of the skin and multiple organs. Early disease may manifest as more inflammatory changes than fibrosis in the skin, joints, and organs; however, this usually progresses rapidly to fibrosis. Table 9 lists the clinical characteristics of scleroderma and its protean manifestations.

Table 9

Clinical Characteristics of Scleroderma

Organ System	Clinical Findings^a
Skin	Thickening
	Pigmentation changes
	Calcinosis
Musculoskeletal	Arthralgia
	Synovitis
	Tendinitis/rubs
	Muscle atrophy
	Contracture
Vascular	Raynaud phenomenon
	Digital ischemia/ulceration
	Abnormal nail-fold capillaries
	Impotence
	Cardiac conduction abnormalities
	Pericardial effusion
	Congestive heart failure
Renal	Renal crisis
	Renal failure
Lung	Dyspnea
	Chronic cough
	Pulmonary hypertension
	Interstitial lung disease
Gastrointestinal	Dysphagia
	Gastroesophageal reflux
	Constipation
	Diarrhea
	Malabsorption
	Bacterial overgrowth syndrome

^aIn order of approximate frequency for each organ system.

Patients can present with skin thickening, but often this can be subtle or go unnoticed. Subtle facial changes can manifest as inability to open the mouth fully when eating. Early skin disease can be edematous or pruritic.

Raynaud phenomenon is present in almost all patients at some time in the course of disease and is often the initial manifestation. Symptoms of gastrointestinal reflux are common in the general population, but also can be an early manifestation of scleroderma. Pulmonary symptoms, such as cough and dyspnea, can be manifestations of gastrointestinal or pulmonary disease. Pain and arthralgias are common early symptoms.80

The Criteria for the Classification of Systemic Sclerosis, created in 1980 by the American College of Rheumatology, show a sensitivity of 97% and specificity of 98% with the presence of the major or at least 2 minor criteria.81 The major criterion is symmetric sclerosis—skin thickening of the hands, extremities, face, neck, and trunk. The minor criteria are sclerodactyly (ie, thickening limited to the fingers and/or toes), digital pitting or loss of finger pad substance, and bilateral basilar pulmonary fibrosis.

These criteria are most useful in classifying patients for inclusion in clinical studies. In practice, many patients have more subtle symptoms of scleroderma that might not precisely match the formal definition of the disease.

Scleroderma Subtypes

The 2 most widely accepted subtypes of scleroderma are limited and diffuse, as shown in Table 10.82 These terms can be confusing because several types of limited scleroderma have been recognized.

Table 10

Scleroderma Subtypes

	Subtype
System	Diffuse	Limited
Skin	Distal and proximal	Distal (to elbows)
	Face and trunk	Face
Raynaud phenomenon	Onset within 1 year after skin changes	Precedes skin changes by more than 1 year
Fingernail fold	Capillary dilatation and dropout	Capillary dilatation with little or no dropout
Visceral	Significant pulmonary, cardiac, gastrointestinal, or renal involvement	Pulmonary hypertension and/or gastrointestinal involvement
Immune (ie, autoantibodies)	Antitopoisomerase-1	Anticentromere

Information from LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202-205.

One type is referred to as localized scleroderma, which does not include internal organ disease and manifests only as skin involvement. Skin findings are most common in morphea (ie, isolated thick, hardened patches of skin) or linear scleroderma (ie, bands of hard skin across the arm or face, often starting in childhood). Localized scleroderma should be considered a separate condition from systemic scleroderma.

Another type of limited scleroderma is CREST syndrome, in which patients develop calcinosis of soft tissues; Raynaud phenomenon; esophageal dysfunction; sclerodactyly (ie, thickening of the digits of the hands and feet); and telangiectasia of the face, trunk, hands, and lips. Another type of limited scleroderma is systemic sclerosis sine scleroderma, a more severe condition in which patients have fibrosing visceral disease but no skin manifestations.

Patients often have incomplete forms of scleroderma. Others have overlap with related connective tissue diseases (CTDs), such as rheumatoid arthritis, systemic lupus erythematosus (SLE), or polymyositis.

Epidemiology, Etiology, and Mortality

Estimates of incidence and prevalence of scleroderma vary but have been estimated at 20 patients per 1 million and 250 patients per 1 million, respectively.83 There is approximately a fivefold increased risk in women.

Genetic and environmental factors have been linked to increased risk of scleroderma, but there is a low rate of disease concordance (4.6%) in monozygotic twins. On the other hand, there is an increased relative risk of 13 for patients with a first-degree relative with scleroderma.83,84 Proposed genetic factors include B- and T-cell markers, cytokine and chemokine molecules and receptors, and extracellular matrix proteins. Transforming growth factor-beta has been implicated because of its association with fibrosis.

Because of the low rate of concordance in twins, environmental factors are thought to play a significant role. Toxic exposures (eg, canola oil contaminated with aniline) and low-level exposures to solvents may also increase this risk.85 Several infectious agents have been considered as factors.

In a large US study, survival rates among patients with scleroderma were estimated at 78% at 5 years, 55% at 10 years, 37% at 15 years, and 27% at 20 years.84 Increased mortality risk is associated with the more severe forms of scleroderma.86 Rapid skin thickening has been associated with increased mortality risk, but likely also reflects greater involvement of the lungs, heart, and kidneys. Esophageal involvement is less strongly correlated with increased mortality risk.

Currently, approximately 60% of patients with scleroderma die from pulmonary disease, either pulmonary hypertension or pulmonary fibrosis.84,86 In the past, scleroderma-related renal failure was the most common cause of mortality. The incidence of renal failure has decreased with the common use of angiotensin-converting enzyme (ACE) inhibitors.

Diagnostic Tools

Durometer

A common presentation of scleroderma is sclerodactyly, appearing as subtle thinning of the folds of skin overlying the knuckles. The classic method of assessing skin involvement in scleroderma is the modified Rodnan skin score, which uses a subjective 3-point scale at 17 body sites.87

More recently, use of a durometer, which measures elastic properties of materials, to obtain a more objective measurement of skin elasticity has been shown to be accurate, sensitive, and reflective of patient self-assessment of disease.88 Development of sclerodactyly is slow and subtle, as are changes in the skin when therapy is effective. Use of a durometer is a sensitive method for detecting skin changes and monitoring treatment.

Fingertip Lacticemy

Diagnosis of Raynaud phenomenon requires at least 2 of 3 color changes in fingers or toes in response to cold exposure or emotion and, as determined by patient history or physician observation, presence of pallor, cyanosis, and reactive hyperemia.89 A more objective test, cold-stimulus fingertip lacticemy, measures lactate in blood obtained from a finger stick during a cold-water challenge.90 In addition to its usefulness in diagnosis, cold stimulus fingertip lacticemy can help measure response to calcium channel blocker treatment. Further, results can be used to differentiate patients with idiopathic Raynaud phenomenon from those with scleroderma.

At this point, the test is not in regular clinical use because the measured changes in lactate levels, although statistically significant, have been small. This technique shows promise but requires additional refinement before becoming a routine tool.

Capillaroscopy

Patients with scleroderma often have enlarged capillaries at the nail folds.91 Capillaroscopy, which provides a magnified view of those capillaries, can be performed using specialized equipment and digital photography. However, capillaroscopy also can be performed easily in the office setting using an ophthalmoscope set on 40x. Presence of a single engorged capillary in a patient with Raynaud phenomenon should warrant a more intensive investigation for scleroderma.

Antinuclear Antibodies

Almost all patients with scleroderma have positive results for antinuclear antibodies (ANAs) on testing.92 A nucleolar pattern is most common and is present in 30% of these patients. When further testing is obtained for individual extractable nuclear antigens, several findings are typical. Specifically, antitopoisomerase-1 antibodies (anti-Scl 70) are associated with the diffuse form of scleroderma. These are present in 40% of patients with scleroderma and may be a significant predictor of more severe disease.

Anticentromere antibodies are present in 75% of patients with the limited form of scleroderma and CREST syndrome. Antiribonucleoprotein antibodies are found in almost all patients with mixed CTD with features of overlap between limited scleroderma, rheumatoid arthritis, SLE, and polymyositis.

Antiphospholipid Antibodies

Antiphospholipid antibodies are associated with thromboembolic disease in primary antiphospholipid syndrome and in SLE, but they can also occur in scleroderma. One study focused on patients with scleroderma and digit loss because of severe digital ischemia.93 The study results showed higher prevalence of the antiphospholipid antibodies to beta-2-glycoprotein I among these patients, with an odds ratio (OR) of 2.4 for digit loss and 9.4 for digital ischemia. No association was found with the presence of anticardiolipin antibodies.

Higher ORs of more severe pulmonary hypertension (OR = 4.8) and increased mortality risk (OR = 2.9) were found among patients with antibodies to beta-2-glycoprotein I. It is unknown if these antibodies are pathogenic or an epiphenomenon; further studies are needed.

Approach to Monitoring Disease

Routine Testing

Predictors of poor prognosis include diffuse skin involvement, older age, black or American Indian ancestry, pulmonary diffusion capacity less than 40% of predicted, large pericardial effusion, proteinuria, hematuria, renal failure, anemia, elevated erythrocyte sedimentation rate (ESR), and abnormal electrocardiogram (ECG) results. Thus, it is recommended that complete blood count, creatinine level, ESR, urinalysis, ECG, echocardiogram, and pulmonary function tests be obtained every 6 months.

Antinuclear Antibodies

Most ANA levels are not monitored because they do not usually change with disease state. However, the anti-Scl 70 level may correlate with disease activity.94 Monitoring the serum N-terminal pro-brain natriuretic peptide level can be useful because levels may correlate with early pulmonary hypertension.95

Pulmonary Fibrosis

Bilateral basilar pulmonary fibrosis is the third minor criterion for scleroderma diagnosis. It is defined as a bilateral reticular pattern of linear or lineonodular densities that are most pronounced in basilar portions of the lungs on standard chest x-ray.

Pulmonary disease has become the most significant cause of mortality in patients with scleroderma, both from pulmonary fibrosis and pulmonary hypertension. Pulmonary disease also contributes to significant morbidity and disability among these patients. The availability of high-resolution computed tomography (HRCT) scan of the lung has allowed for more effective imaging of architectural changes in the lung.

Most studies using HRCT scanning have been small. One study associated with a prospective clinical trial evaluated HRCT scan results for 162 patients from 13 centers.96 It compared patients with symptomatic lung disease with dyspnea and with either diffuse or limited scleroderma.

Pulmonary fibrosis was present in 93% of patients, ground-glass opacities or increased attenuation without architectural distortion in 49%, and honeycomb cysts in 37%. More honeycomb cysts were found in patients with limited scleroderma. The extent of pulmonary fibrosis was inversely correlated with pulmonary function test results, and ground-glass opacities were correlated with increased inflammatory cells from bronchiolar lavage.

Pulmonary status should typically be monitored every 6 months, either with pulmonary function tests or HRCT scans. HRCT scan may offer higher sensitivity for detection of changes compared with routine pulmonary function tests, but would result in considerable radiation exposure.

Treatment

Scleroderma is not curable, but certain treatments can be helpful for many patients. General measures should be considered, such as counseling regarding adequate nutrition, exercise, physical and occupational therapies, emotional support, and treatment for depression.

In 2009, using a review of clinical trials along with clinical consensus, the European Union League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) prepared guidelines for scleroderma management.97 These are summarized in Table 11.

Table 11

EULAR Recommendations for Scleroderma Treatment

Symptom or Condition	Treatment
Diffuse skin involvement	Methotrexate
Digital ulceration	Oral nifedipine for initial therapy, intravenous iloprost for severe disease decreases frequency and severity of symptoms Intravenous iloprost for active disease Bosentan to prevent disease
Interstitial lung disease	Cyclophosphamide
Pulmonary hypertension	Bosentan improves functional class and exercise capacity Sildenafil improves functional class and exercise capacity Intravenous continuous epoprostenol improves functional class and exercise capacity
Renal crisis	ACE inhibitors for treatment and prevention Steroids increase the risk of renal crisis, monitor for hypertension
Gastrointestinal	Proton-pump inhibitors to prevent GER, stricture Prokinetic drugs for early satiety, bloating, pseudo-obstruction Rotating antibiotics for malabsorption due to bacterial overgrowth

ACE = angiotensin-converting enzyme; EULAR = European League Against Rheumatism; GER = gastroesophageal reflux.

Information from Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68(5):620-628.

Arthralgias

Arthralgias can be managed with nonsteroidal anti-inflammatory drugs (NSAIDs); hydroxychloroquine; or an immunomodulatory drug, such as methotrexate, azathioprine, or mycophenolate mofetil.97 These are used in an ascending intensity of treatment. Inflammatory episodes can be managed with steroid burst and taper dosages. However, steroid use can increase the risk of renal failure, often with marked hypertension. Management with NSAIDs, hydroxychloroquine, or an immunomodulatory drug is preferable. A patient with scleroderma and any signs of hypertension should be taking an ACE inhibitor to provide renal protection.

Gastrointestinal Conditions

Esophageal reflux disease due to esophageal motility dysfunction is common and should be managed with a proton-pump inhibitor. Diarrhea secondary to bacterial overgrowth syndrome should be managed with antibiotics.

Raynaud Phenomenon

Raynaud phenomenon can be idiopathic or associated with several autoimmune diseases and is almost always present in patients with scleroderma. For mild symptoms without fingertip ulcerations, behavioral modifications, such as wearing gloves and maintaining adequate body core temperature, are sufficient.

Painful episodes, particularly leading to fingertip ulcerations, can be disabling and require preventive treatment. The first-line choice is a calcium channel blocker, usually extended-release nifedipine or amlodipine.98

Treatment beyond calcium channel blockers includes intravenous iloprost and sildenafil.99 One study showed that a low dose of intravenous iloprost, 25% of the usual maximum dose, was as effective as the usual dose, though the study only lasted 21 days.100 In patients with Raynaud phenomenon that is resistant to therapy, bosentan can be used.101

One study evaluated the use of statin therapy in patients with limited scleroderma, ongoing Raynaud phenomenon, and digital ulcerations despite ongoing vasodilator therapy.102 The number of new ulcerations decreased and general markers of disease activity improved with statin therapy. Although this was a small study of 40 patients, this low-cost, low-toxicity treatment should be considered when vasodilator therapy is ineffective.

Pulmonary Disease

Active inflammatory pulmonary disease in scleroderma is commonly treated with cyclophosphamide. The most effective route of administration for cyclophosphamide and subsequent therapy has not been well investigated.

One study examined the use of oral cyclophosphamide daily for 1 year without subsequent maintenance therapy, and monitored patients for an additional year.103 This therapy showed benefit for lung function, skin scores, dyspnea, and general function at 1 year. However, only improvements in dyspnea continued to the end of the next year after completion of therapy. Another consideration would be to manage scleroderma in a manner similar to lupus nephritis, with 6 months to 1 year of monthly intravenous cyclophosphamide, followed by maintenance therapy with mycophenolate.

Skin Disease

Small studies have shown methotrexate, mycophenolate, rituximab, and autologous stem cell transplantation to be beneficial in skin disease treatment.104,105,106 Another study focused on topical treatment of localized scleroderma (morphea) using tacrolimus.107 Although this was found to be effective, only 2 areas of localized skin were treated. These study results may not translate into treatment of systemic disease with widespread skin lesions.

A double-blind placebo-controlled study evaluated the possibility of inducing immune tolerance to collagen.108 Native bovine collagen was administered to 168 patients by mouth daily for 12 months. The study did not show benefit using the predetermined end point, but exploratory statistical analyses found some patients with late-phase disease showed some acceleration of skin softening.

Case 3, cont’d. You think Alex likely has scleroderma. Assuming no toxin exposure has occurred, you proceed with an initial evaluation that includes complete blood count (CBC), testing for Sjögren syndrome A and B, and measurement of the following: serum creatinine, creatinine kinase, aspartate aminotransferase, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANAs), anti-Scl 70, anticentromere antibodies, antiribonucleoprotein antibodies, antiphospholipid antibodies, and lipid levels. Urinalysis, electrocardiogram (ECG), echocardiogram, pulmonary function tests, and a high-resolution computed tomography (HRCT) scan of the lungs are also obtained.

The CBC results show mild anemia that does not require treatment. The ANA titer is positive (1:320 in a speckled pattern) and anti-Scl 70 test results are positive. The HRCT scan shows very mild fibrosis, and pulmonary function test results are normal. The other test results are normal or negative.

You give Alex a calcium channel blocker to manage the Raynaud phenomenon, and you consider statin therapy. You decide to manage the arthralgias with mycophenolate mofetil, with follow-up to ensure this is an effective treatment.

You plan to monitor Alex by taking the history and performing a physical examination every 2 to 3 months. Also, every 6 months, Alex will undergo a CBC, creatinine level and ESR measurements, urinalysis, ECG, echocardiogram, and either pulmonary function tests or HRCT scan of the lungs. The risk of his children developing scleroderma is very low.

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Online Resources

Arthritis Foundation

http://www.arthritis.org
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http://www.hopkins-arthritis.org/
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

http://www.nih.gov/niams/

Connective Tissue Diseases

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