The American College of Rheumatology criteria and SLICC criteria for the classification of SLE apply to epidemiological surveys and inclusion in clinical trials. Patients can have lupus without fulfilling the criteria. Physicians use a variety of parameters to make clinical decisions regarding lupus patients.4-6 These include the following:
• Symptoms (e.g., stiffness, aching, fatigue)
• Signs (e.g., rashes, synovitis)
• Laboratory abnormalities (e.g., anemia, elevated sedimentation rate)
• Serological abnormalities (e.g., elevated anti-DNA)
• Electrical abnormalities (e.g., EKG [ECG], EEG, EMG)
• Imaging abnormalities (e.g., chest radiograph, 2-D echocardiography, computed tomography scanning, or magnetic resonance imaging)
In 2010, the U.S. Food and Drug Administration issued a Guidance Document, which provided a guide to clinical investigators for clinical trials.1 Among its recommendations the document relates that the following factors are acceptable means for demonstrating the efficacy and safety of a specific intervention:
• The drug is safe.
• Quality of life is improved (e.g., Lupus PRO).
• A validated clinical index demonstrates less disease activity (e.g., the BILAG and either the SLEDAI or the SLAM)2,3 (Fig. 9.1, Table 9.1). The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) takes less than a minute to calculate; the majority of its values relate to the central nervous and renal systems. It fails to include many manifestations of the disease and deem-phasizes laboratory abnormalities. The British Isles Lupus Assessment Group (BILAG) is extremely complex and thorough but is not subject to consistently reliable statistical analysis, while the Systemic Lupus Activity Measure (SLAM) includes subjective components. Hence, most clinical trial designs utilize at least two of these metrics.
• A response measure demonstrates improvement (e.g., the SLE Responder Index) (Fig. 9.2).6
• There is less advancement of scarring or damage (e.g., SLICC/ACR Damage Index).4
• Trials should be of one year duration in patients stratified by severity, with flares, responses, and steroid sparing carefully defined.
• There are organ-specific measures (e.g., CLASI for cutaneous disease,5 renal indices).
• No surrogate markers or biomarkers are yet acceptable in ascertaining and following disease activity, but promising prospects (e.g., the interferon signature) could be acceptable metrics to shorten the length of clinical trials.
Figure 9.1 The 2004 British Isles Lupus Assessment Group (BILAG) checksheet form. This version of the form is the one currently used in most ongoing clinical trials.
Figure 9.2 The SLE Responder Index.6
Table 9.1 SELENA-SLEDAI Index
|
Weight |
Descriptor |
Definition |
|
8 |
Seizure |
Recent onset (last 10 days). Exclude metabolic, infectious drug cause, or seizure due to past irreversible CNS damage. |
|
8 |
Psychosis |
Altered ability to function in normal activity due to severe disturbance in the perception of reality. Include hallucinations, incoherence, marked loose associations, impoverished thought content, marked illogical thinking, bizarre, disorganized, or catatonic behavior. Exclude uremia and drug causes. |
|
8 |
Organic Brain Syndrome |
Altered mental function with impaired orientation, memory, or other intellectual function, with rapid onset and fluctuating clinical features. Include clouding of consciousness with reduced capacity to focus and inability to sustain attention to environment, plus at least 2 of the following: perceptual disturbance, incoherent speech, insomnia or daytime drowsiness, or increased or decreased psychomotor activity. Exclude metabolic, infectious, or drug causes. |
|
8 |
Visual Disturbance |
Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, serious exudate of hemorrhage in the choroid, optic neuritis, seleritis, or episcleritis. Exclude hypertension, infection, or drug causes. |
|
8 |
Cranial Nerve Disorder |
New onset sensory or motor neuropathy involving cranial nerves. Include vertigo due to lupus. |
|
8 |
Lupus Headache |
Severe persistent headache: may be migrainous, but must be non-responsive to narcotic analgesia. |
|
8 |
Cerebrovascular Accident (CVA) |
New onset of CVA(s). Exclude arteriosclerosis or hypertensive causes. |
|
8 |
Vasculitis |
Ulceration, gangrene, tender finger nodules, periungual infarction, splinter hemorrhages, or biopsy or angiogram proof of vasculitis. |
|
4 |
Arthritis |
More than 2 joints with pain & signs of inflammation (i.e., tenderness, swelling or effusion). |
|
4 |
Myositis |
Proximal muscle aching/weakness associated with elevated creatine phosphokinase/aldolase or electromyogram changes or a biopsy showing myositis. |
|
4 |
Urinary Casts |
Heme-granular or red blood cell casts. |
|
4 |
Hematuria |
>5 red blood cells/high power field. Exclude stone, infection, or other causes. |
|
4 |
Proteinuria |
New onset or recent increase of more than 0.5 g/24 hours. |
|
4 |
Pyuria |
>5 white blood cells/high power field. Exclude infection. |
|
2 |
Rash |
New or ongoing inflammatory lupus rash. |
|
2 |
Alopecia |
New or ongoing abnormal, patchy or diffuse loss of hair due to active lupus. |
|
2 |
Mucosal Ulcers |
New or ongoing oral or nasal ulcerations due to active lupus. |
|
2 |
Pleurisy |
Classic and severe pleuritic chest pain or pleural rub or effusion or new pleural thickening due to lupus. |
|
2 |
Pericarditis |
Classic and severe pericardial pain or rub or effusion, or electrocardiogram confirmation. |
|
2 |
Low Complement |
Decrease in CH50, C3, or C4 below the lower limit of normal for testing laboratory. |
|
2 |
Increased DNA Binding |
>25% binding by Farr assay or above normal range for testing laboratory. |
|
1 |
Fever |
>38°C. Exclude infectious cause. |
|
1 |
Thrombocytopenia |
<100,000 platelets/mm3 |
|
1 |
Leukopenia |
<3,000 white blood cells/mm3. Exclude drug causes. |
|
TOTAL SCORE |
(Sum of weights next to descriptors marked present) |
|
|
Score if descriptor is present at time of visit or in the preceding 10 days. SLEDAI—Systemic Lupus Erythematosus Disease Activity Index SELENA—Selective use of Estrogens in Lupus Erythematosus National Assessment |
||
Lupologists are in the process of reconfiguring how they follow their patients and what parameters are used in the clinic on the basis of information derived from clinical trials.
References
1. U.S. Food and Drug Administration. Guidance for Industry on Systemic Lupus Erythematosus: Developing Medical Products for Treatment. Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07263.pdf. Accessed March 11, 2013.
2. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288–291.
3. Yee CS, Farewell V, Isenberg DA, et al. British Isles Lupus Assessment Group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum. 2007;56:4113–4119.
4. Gladman DD, Goldsmith CH, Urowitz MB, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison. J Rheumatol. 2000;27:373–376.
5. Klein R, Moghadam-Kia S, LoMonico J, et al. Development of the CLASI as a tool to measure disease activity and responsiveness to therapy in cutaneous lupus erythematosus. Arch Dermatol. 2011 Feb;147(2):203–208.
6. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009 Sep 15;61(9):1143–1151.