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Best Practice & Research Clinical RheumatologyVol. 21, No. 4, pp. 687–697, 2007
doi:10.1016/j.berh.2007.01.003available online at http://www.sciencedirect.com
8
Monitoring systemic lupus erythematosus
in standard clinical care
Michelle Petri* MD, MPH
Professor of Medicine
Johns Hopkins University School of Medicine, 1830 E Monument St Suite 7500, Baltimore, MD 21205, USA
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a fluctuating andunpredictable course. Monitoring SLE in the routine clinic setting is a challenge because both thedisease and its treatment can result in organ damage. Disease activity indices and a cumulativehistory summary can be used to track complicated patients over time. Monitoring guidelines fordamage from the disease and for the toxicity of treatment are available.
Key words: flare; organ damage; SLE.
INTRODUCTION
Systemic lupus erythematosus (SLE) is always challenging for the clinician. Not only canit affect almost any organ system but it is often difficult to determine whether organdysfunction is due to disease activity, organ damage, or both. Both SLE and its treat-ment can permanently damage organs. The quality of life in SLE is poor, leading tosocial and disability issues. This chapter addresses each domain of SLE: disease activity,organ damage, and quality of life, in terms of their monitoring in standard clinical care.The use of disease activity indices in the clinic and of a cumulative history summary totrack complicated patients over time is discussed and summaries of monitoring guide-lines for damage from the disease and for the toxicity of its treatments included.
DISEASE ACTIVITY
SLE activity has three general patterns: ‘flare’ (or ‘relapsing remitting’), ‘chronic’ activ-ity, or ‘long quiescence’ (or ‘remission’).
* Tel.: þ1 410 955 3823; Fax: þ1 410 614 0498.
E-mail address: [email protected].
1521-6942/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
688 M. Petri
In the flare pattern, patients are usually well inbetween exacerbations.1 Theexacerbations occur suddenly and unpredictably, sometimes overnight. Precipitantsof flare are often not identified but can include ultraviolet light, the use of drugs ornutriceuticals that ‘activate’ the immune system (e.g. echinacea), infections, surgery,pregnancy, and sulfonamide antibiotics. One of the most common precipitants of flareis non-compliance with maintenance therapy (which includes hydroxychloroquine, cor-ticosteroids, and immunosuppressive drugs). Serologic tests tend not to be very usefulin predicting flare at the next visit. At the time of the flare, anti-dsDNA in the serumtends to decrease2, probably due to the deposition of immune complexes in organs.Serum complement levels fall at the time of a hematologic or renal flare3, but the flareitself is diagnosed by routine laboratory testing, not the change in serology. Serologictests can be abnormal for long periods in patients with no evidence of flare, theso-called ‘serologically active but clinically quiescent’ (SACQ) patient.4 However, a pa-tient with low complement or high anti-dsDNA is more likely to flare over the next year.
Another large group of SLE patients has chronic activity. This includes SLE patientswith chronic synovitis and chronic cytopenias, and those who always have somedegree of active discoid lupus. Chronic cytopenias, such as leukopenia and thrombo-cytopenia, do not always require treatment.
Finally, a minority of SLE patients achieve a period of long quiescence, some foryears. It might not be valid to use the term ‘remission’, in that many of these patientshave a later return of disease activity.
MONITORING DISEASE ACTIVITY
A stable SLE patient can be seen at quarterly intervals. An unstable SLE patient mightrequire weekly follow-up. At each visit, an interval history is necessary. Because SLEcan change over time, it is very helpful to have a summary sheet of past organ man-ifestations. An example of the Hopkins Lupus Cohort cumulative history form isshown in Figure 1. In a complicated patient, such a historical summary can avoid theneed for large paper charts and for reviewing multiple notes in an electronic patientrecord.
The physical examination needs to be extensive and to include skin, mucous mem-branes, lymph nodes, chest, heart, abdomen, extremities, and the musculoskeletal andneurologic systems. The pertinent findings to assess are shown in Table 1.
Monitoring lupus activity requires laboratory testing (Table 2). Routine laboratorytesting should include a complete blood count (CBC), platelet count, creatinine, liverfunction tests, and urinalysis. It is important to check the anitphospholipid status(lupus anticoagulant and anticardiolipin) periodically. For some patients, the erythrocytesedimentation rate (ESR), complement (C3, C4), and anti-dsDNA are informative.
Special monitoring is required during pregnancy. At the first pregnancy visit, anti-Roand anti-La are measured. If positive, weekly fetal four-chamber cardiac ultrasoundsare scheduled from week 16 to week 32 of the pregnancy to detect congenital heart
Practice points
� Disease activity in SLE can follow a flare or chronic activity pattern.� Serologic activity without clinical activity occurs frequently in SLE.
Monitoring in systemic lupus erythematosus 689
block.5 Uric acid6 and/or urine calcium can be monitored to detect pre-eclampsia. Lowcomplement or high anti-dsDNA, in the setting of lupus activity, are highly predictiveof preterm birth.7
Monitoring of renal lupus includes urinalysis and measurement of serum creatinineand urine protein. Although an American College of Rheumatology position paper
Figure 1. Cumulative systemic lupus erythematosus history of organ involvement and manifestations.
690 M. Petri
recommended using the spot urine protein to creatinine ratio to monitor lupusnephritis8, the spot urine is inadequate for clinical care. Because of a diurnal rhythmin proteinuria, and changes in posture, diet, and exercise, the spot urine protein tocreatinine ratio varies during the day.9 The best test to monitor proteinuria is the
Table 1. Physical examination in systemic lupus erythematosus.
Organ system Pertinent features
Skin Examine for malar rash, discoid lupus, alopecia
HEENT Examine for parotid enlargement, cervical lymphodenopathy, nasal sores, oral
sores, salivary pool
Chest Examine for dullness indicative of pleural effusion, bibasilar crackles indicative
of interstitial lung disease, pleural rub
Cardiac Examine for pericardial rub, pulmonary hypertension (accentuated P2), new
cardiac murmur
Abdomen Examine for tenderness or rebound indicative of mesenteric vasculitis,
hepatomegaly, splenomegaly
Extremities Examine for livedo reticularis, Raynaud’s phenomenon, digital vasculitis,
arterial pulses
Musculoskeletal Examine for inflammatory synovitis, pain in joints indicative of osteonecrosis,
and fibromyalgia tender points
Neurological Examine for cognitive impairment, optic neuropathy, peripheral neuropathy,
mononeuritis multiplex, transverse myelitis, weakness, numbness
indicative of stroke
HEENT, head, eyes, ears, nose, throat.
Table 2. Laboratory monitoring in systemic lupus erythematosus.
Routine visits CBC
Platelet count
Creatinine
Liver function tests
Urinalysis
Periodic checks Lupus anticoagulant, anticardiolipin
Pregnancy monitoring CH50, C3, C4
Uric acid
Anti-Ro, anti-La
Select patients ESR
C3, C4
Anti-dsDNA
Renal lupus monitoring 24-hour urine protein/creatinine ratio
Toxicity monitoring Methotrexate: CBC, platelets, liver function tests
Azathioprine:CBC, platelets, liver function tests, amylase
Mycophenolate mofetil: CBC, platelets, liver function tests
Leflunomide: CBC, platelets, liver function tests
CBC, complete blood count; ESR, erythrocyte sedimentation rate.
Monitoring in systemic lupus erythematosus 691
24-hour urine protein to creatinine ratio.10 A 24-hour urine protein alone is not asaccurate as the ratio because the 24-hour collection is often over- or under-reported.
DISEASE ACTIVITY INDICES
To be used in standard clinical care, a disease activity index (DAI) must be short andeasy to complete. Several such indices have been developed for use in the routineclinic setting. One, the Lupus Activity Index, is a visual analog scale for the physi-cian’s estimate of activity overall and for individual organs.11 A second practicalDAI is the SLEDAI and its updated versions – the SELENA-SLEDAI12 and theSLEDAI-2K.13 Both types of DAI make it possible to summarize on one page thedisease activity in multiple organs. More complicated DAIs, such as the British IslesLupus Activity Group (BILAG)14,15, are better relegated to clinical research becausethey require computer software to facilitate scoring. An example of incorporationof DAIs into routine clinic practice is shown in Figure 2. The Lupus Activity Index,SLEDAI, and Infection History descriptors comprise the bottom half of the encoun-ter form.
Organ damage
More than 50% of SLE patients suffer permanent organ damage. Accrual of organ dam-age increases the risk of mortality. It has been reported that over 75% of organ damageis due – directly or indirectly – to corticosteroids.13 The most common organ systemsdamaged in the Hopkins Lupus Cohort are shown in Table 3. In complicated patients,the SLICC Damage Index can help to summarize permanent damage, both for pur-poses of clinical care and also for use when completing disability forms.16 Monitoringfor, and prevention of, organ damage are summarized in Table 4.
Musculoskeletal damage
More than 90% of SLE patients take prednisone. Even low, physiologic doses of pred-nisone increase the risk of osteoporotic fractures.17 Active lupus can also contributeto osteoporosis through inflammatory cytokines, including interleukin-6 (IL-6). Allpatients with SLE should follow the American College of Rheumatology guidelineson osteoporosis.18 This means that patients on prednisone should also be on calciumand vitamin D. Dual energy X-ray absorptiometry (DEXA) monitoring is recommen-ded every 2 years. Women with osteopenia or osteoporosis are candidates forbisphosphonates, provided that they do not have renal insufficiency/failure and donot plan on a later pregnancy. Men with osteopenia/osteoporosis should have totaland free testosterone checked, and begin replacement therapy if levels are low.DHEA has a beneficial effect on bone19 and can be considered in women who planlater pregnancies; there is no information on its use in pregnancy itself.
Osteonecrosis, or avascular necrosis of bone, can occur with prednisone dosesgreater than 20 mg daily. It is more common in African–Americans than in Cauca-sians.20 The most common joints affected are hips, knees, and shoulders andthe condition is usually bilateral. Hip pain that is not local trochanteric bursitisshould trigger a hip MRI. If osteonecrosis is present at an early stage before collapseof the femoral head, then core decompression might save the joint provided the
692 M. Petri
prednisone can be tapered.21 To detect asymptomatic joints with osteonecrosis,a bone scan is necessary. Bisphosphonates can occasionally cause osteonecrosis ofthe jaw.22 Antibiotics are recommended if patients on bisphosphonates undergodental surgery.
Name _______________ __________________ History #: Date:First Last
Next Visit:History: _________________________________________________________________________________ Wt __________
_________________________________________________________________________________ T ___________________________________________________________________________________________ BP ____________________________________________________________________________________________________________________________________________________________________________ Pain _______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
PE: skin: ____________________________________________________________HEENT: ____________________________________________________________Chest: ____________________________________________________________Cor: ____________________________________________________________abd: ____________________________________________________________ext: ____________________________________________________________musculoskel: ____________________________________________________________neuro: ____________________________________________________________
Impression: __________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________
Lupus Activity IndexPhysician Estimate of Activity (0,none-3,max) 0 1 2 3
Symptoms1. fatigue ____
0 1 2 3 2. rash ____
0 1 2 3 3. joints ____
0 1 2 3 4. serositis ____
0 1 2 3 System involvement
1. neurologic ____ 0 1 2 3
2. renal ____ 0 1 2 3
3. pulmonary ____ 0 1 2 3
4. hematologic ____ 0 1 2 3
Raynaud’s 0 1 2 3
SLEDAICNS
1. seizure 2. psychosis 3. OBS 4. visual5. cranial nerve 6. lupus 7. CVA headache
Vascular 1. vasculitis Renal
1. casts 2. hematuria 3. proteinuria 4. pyuria
Musculoskeletal 1. Arthritis 2. Myositis
Immunology Lab1. Low complement 2. DNA
1. New (recur) rash 2.Alopecia3. Mucous membrane
Serositis1. Pleurisy 2.Pericarditis
Hematology Lab1. PLTS<100 2. WBC<3
Constitutional 1. Fever
ALLERGIES : ___________________ _______________________________ _______________________________ _______________________________ _______________________________
Infection HistoryViral infection ____+/-____wksBacterial infection ____+/-____wksThrush ______ Opportunistic ________
TreatmentPrednisone, mg/day ______________
Triamcinolone IM ______________IV solumedrol ______________
Cytotoxic ______________Plaquenil ______________NSAID ______________
ASA _______ plavix ____________Anti-HTN - diuretic ______________
ACE-inhib or ARB ______________Ca channel ______________Other _____________
DHEA ______________B-vitamin or MVI ______________Osteoporosis – Ca/D ______________
bisphosphonate ______________Hormones ______________Thyroid ______________Anti-depressant ______________Pain (narcotic) ______________Statins ______________Asthma ______________GI meds ______________Coumadin/Heparin ______________Other ___________ _____________
___________ _____________
Skin
________________ _____ / _____ / _____
Figure 2. Systemic lupus erythematosus encounter form.
Practice points
� Musculoskeletal damage is the most common organ damage in SLE.� Osteoporotic fractures and osteonecrosis are secondary to corticosteroid use.
Monitoring in systemic lupus erythematosus 693
Neurologic damage
Approximately 50% of strokes in SLE occur in patients with antiphospholipid anti-bodies. SLE patients known to have moderate- to high-titer IgM or IgG anticardiolipin,anti-beta-2 glycoprotein I, or the lupus anticoagulant are candidates for low-dose as-pirin. However, there is no evidence that aspirin is an effective prophylactic therapy.23
Table 3. Organ damage in the Hopkins lupus cohort.
Type of damage Percentage of cohort
Musculoskeletal 25.2%
Neuropsychiatric 15.0%
Ocular 12.6%
Renal 11.7%
Pulmonary 10.4%
Cardiovascular 10.1%
Gastrointestinal 7.4%
Skin 7.4%
Peripheral vascular 5.5%
Diabetes mellitus 6.1%
Malignancy 2.5%
Premature gonadal failure 1.2%
Table 4. Monitoring (M) for and prevention (P) of organ damage.
Type of damage Specific damage Monitoring and prevention
Musculoskeletal Osteoporosis M: DEXA every 2 years if taking prednisone
P: vitamin D, calcium supplementation
Osteonecrosis M: MRI; bone scan for asymptomatic joints
P: keep prednisone dose below 20 mg
Neurologic Stroke P: low-dose aspirin in antiphospholipid-positive
patients
Cognitive impairment P: low-dose aspirin in antiphospholipid-positive
patients
Ocular Cataracts M: yearly ophthalmology examination
Hydroxychloroquine
retinopathy
M: yearly ophthalmology examination
P: reduce dose in renal insufficiency/failure;
dose by weight
Cardiovascular M: stress cardiac echo, or equivalent, if chest pain
P: strict control of cardiovascular risk factors
Renal M: 24-hour urine protein to creatinine ratio;
urinalysis with microscopic analysis
P: ACE-inhibitor or angiotensin receptor blocker
ACE, angiotensin converting enzyme; DEXA, dual energy X-ray absorptiometry; MRI, magnetic reso-
nance imaging.
694 M. Petri
Homocysteine is strongly associated with stroke and other arterial events in SLE24 butclinical trials in the non-SLE population have not shown any benefit of folic acidsupplementation.25,26
Cognitive impairment is the most frequent neurologic damage in SLE. Ten yearsafter diagnosis, 80% of SLE patients have measurable cognitive impairment.27 Multiplelongitudinal studies have shown that SLE patients with antiphospholipid antibodies aremore likely to have cognitive impairment, and for this to progress28–30; one study hasshown that aspirin might be protective. Depression and fibromyalgia can contribute tocognitive impairment in SLE. Fibromyalgia is the most common reason for chronic painin SLE. The inflammation of SLE is thought to contribute to the ‘re-wiring’ of theperipheral and central nervous systems that characterizes fibromyalgia.31
Ocular damage
Posterior subcapsular cataracts are the most common ocular damage in SLE. Hydrox-ychloroquine retinopathy is extremely rare, occurring in only one out of 5000.Updated guidelines indicate that only yearly monitoring is required.32
Cardiovascular damage
Cardiovascular disease remains the major cause of death in SLE.33 The risk of myocar-dial infarction in women between 35 and 44 years of age is increased 50-fold over thatfor normal women.34 Traditional cardiovascular risk factors do not account entirelyfor the risk.35 Even atypical chest pain should be evaluated in a patient with SLE. Strin-gent control of cardiovascular risk factors is encouraged, but no intervention trialproving benefit has been reported.36,37
Renal damage
Fifty percent of SLE patients will develop lupus nephritis. The best test to monitor lu-pus nephritis is urine protein. To quantitate urine protein, the 24-hour urine protein tocreatinine ratio is preferred over the 24-hour urine, because the latter is often over-or under-collected.10 The spot urine protein to creatinine ratio is affected by time ofday, diet, posture, and exercise, and is not the gold standard.38 Despite aggressive ther-apy, progression to renal failure can occur. Based on studies in non-lupus renal disease(including diabetes and hypertension), angiotensin-converting enzyme (ACE) inhibi-tors39 and angiotensin receptor blockers can reduce proteinuria and progression ofdisease. Neither can be used during pregnancy, including the first trimester.40
Practice points
� Myocardial infarction is increased 50-fold in young women with SLE.� Traditional cardiovascular risk factors play a role, but lupus itself is a risk factor.
Monitoring in systemic lupus erythematosus 695
Premature ovarian failure
As many as 50% of women given intravenous cyclophosphamide will develop prema-ture ovarian failure.41 A prospective trial and a retrospective study have both shownthat Lupron, given 2 weeks before each intravenous infusion of cyclophosphamide, isvery effective in protecting ovarian function.42,43 Lupron can lead to hypercoagulabilityand osteoporosis; initially, it can lead to a temporary increase in fertility.
Quality of life
Quality of life in SLE is significantly reduced compared with the general population andis equivalent to that of other major chronic diseases, including HIV and heart failure.The major quality-of-life concerns in SLE include chronic fatigue and fibromyalgia44,which are not improved by SLE therapy. It is crucial to differentiate fibromyalgiafrom active SLE to spare the patient unnecessary exposure to prednisone and immuno-suppressive drugs. Treatment includes rehabilitation, exercise, and correction of sleepdisturbance.45
CONCLUSION
Although few guidelines have been developed or tested for SLE, there is a general con-sensus on how to monitor SLE, how to monitor and prevent organ damage; and on therole of fatigue and fibromyalgia in the poor quality of life of the average patient with SLE.
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Practice points
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