Recommendation #1: Patient assessment

In addition to the standard care of non-lupus patients of the same age and sex, the assessment of the

SLE patient must include the evaluation of: disease activity by a validated index at each visit, organ

damage annually, general quality of life by patient history and/or by a 0 to 10 Visual Analogue

Scale (VAS- patient global) at each visit, comorbidities and drug toxicity.

The clinical picture of SLE is extremely variable and may be related to disease activity, organ

damage, drug toxicity and quality of life. Many studies have documented poor correlations between

activity, damage, and quality of life, suggesting that these measures assess different aspects of

patient status (1-9). Activity and damage assessment have important prognostic significance as

studies have shown a significant correlation between the degree of activity and the subsequent

development of damage and between early damage accrual and the development of damage and

mortality.

Therefore, many authors have suggested that the assessment of SLE patients should include

measures of disease activity, disease damage, quality of life and drug toxicity (3-5).

In recent years, indices have been developed and validated to measure these parameters (1-34). The

most frequently used activity indices are the British Isles Lupus Assessment Group (BILAG), the

European Consensus Lupus Activity Measurement (ECLAM), the Lupus Activity Index (LAI), the

Systemic Lupus Activity Measure (SLAM), the SIS (SLE Index Score) and the SLE Disease

Activity Index (SLEDAI), and revised versions as SLEDAI-2K and Safety of Estrogen in Lupus

Erythematosus National Assessment (SELENA) SLEDAI. The Systemic Lupus International

Collaborating Clinics (SLICC/ACR) Damage Index has been developed to assess irreversible

damage in SLE patients occurring after disease onset. Recently, SLE- specific indices to assess

patient’s quality of life have been developed and validated as well, although the SF-36 is most

widely used to assess quality of life.

1

Indeed the assessment of activity, damage and quality of life is a part of the routine clinical

evaluation. However, it relies on the physician’s experience and therefore may be subject to

significant inter- as well as intra-rater variability in the absence of appropriate training. Despite

their prognostic role and their use in observational studies and randomized controlled trials, the

limited data available suggest that validated indices are used in a small number of centres in clinical

practice. This might be attributed to issues of feasibility (particularly time required to calculate

indices, not always available during routine assessments) and the need to perform tests which are

not always part of the routine patient assessment (e.g. immunological tests, eye examination etc).

However, the use of validated indices might greatly improve the collection of data, and therefore

the quality, of the assessment made during routine evaluations, and few studies show the feasibility

of performing validated disease activity indices in routine clinical practice (35). Therefore, the

Committee agreed upon recommending the routine assessment of disease activity using any

validated index (global or organ specific) and/or a physician global assessment on a scale from 0 to

3, and an annual assessment of damage with the SLICC/ACR damage index.

In randomized controlled trials, the assessment of quality of life is usually based on the use of the

short form 36 (SF36), and recently SLE- specific indices have been developed (2-8,36-39). These

tools allow a comparison of QoL among patients and centres and therefore their use should be

considered when performing observational studies. However, it was felt that the administration of

these questionnaires in routine clinical practice was unlikely to be feasible, and therefore the

Committee agreed on the routine evaluation of patient’s quality of life based on the patient’s history

or with a 0 to 10 VAS (patient global) at each visit.

Recommendation # 2: Cardiovascular risk factors

At baseline and during follow up at least once a year*:

2

Assess: smoking, vascular events (cerebral/cardiovascular), physical activity, oral

contraceptives, hormonal therapies, and family history of cardiovascular disease.

Blood tests: blood cholesterol, glucose.

Examination: Blood pressure, body mass index (and/or waist circumference).

*Some patients may need more frequent follow-up (i.e. patients on glucocorticoids).

Premature atherosclerosis and increased incidence of cardiovascular disease (CVD) among patients

with SLE are well established (40-89). CVD is an important cause of morbidity and a leading cause

of death of SLE patients (43-51,53). Many authors have reported a higher prevalence of traditional

risk factors among SLE patients. In 1992, Petri et al reported that the prevalence of all CV risk

factors was significantly higher among SLE patients versus age-sex and race matched non-SLE

subjects (general population) (40).

The systematic literature review (SLR) found an increased prevalence of hypertension and

dyslipidemia among SLE patients. The reported prevalence of hypertension among SLE patients

ranges from 14% to 52%, with half of the examined studies reporting a prevalence ≥ 40%. In all the

studies comparing SLE patients with healthy controls, the prevalence of hypertension was

significantly higher in SLE patients (33-52% SLE patients vs 6-35% healthy controls) (40-42, 44-

50, 54, 57, 59-71).

Published data on lipid profiles agree on a high prevalence (ranging from 11.5 to 75%) of

dyslipidemia (most frequently assessing cholesterol levels) in SLE patients. Current prednisone

dose and cumulative prednisone dose have been correlated with total cholesterol levels in different

studies (72-80).

Fewer data are available on whether the prevalence of diabetes (prevalence ranging from 0.9 to

11.2%) or obesity is increased, as only a few studies have shown a higher prevalence among SLE

patients (81-83). No differences have been reported with respect to the general population as far as

smoking habits are concerned (84). It might be expected that SLE patients have a more sedentary

3

life-style; indeed one study reported a 70% of prevalence of sedentary life-style according to the

American Heart Association Guidelines.

Data from the literature have shown that the increased incidence of CVD and premature

atherosclerosis in SLE cannot be fully explained by the traditional CVD risk factors. In fact, it has

been shown that population screening based on Framingham risk equations, when applied to SLE

patients, does not fully explain the cardiovascular risk (90-91). On this basis, SLE could be included

in the group of conditions in which the use of these predictive charts is insufficient. For this reason,

some authors have proposed that SLE should be considered as a coronary heart disease high risk

state (much like diabetes mellitus) and have suggested different targets for risk factor modification

specifically tailored to SLE patients (91-94).

However, at present, agreement exists on the need for monitoring traditional cardiovascular (CV)

risk factors and treating modifiable risk factors according to the existing guidelines.

Based on these data, the assessment of traditional CV risk factors in routine clinical practice is

recommended and should be performed with patient history, patient examination and laboratory

exams (i.e. blood cholesterol and blood glucose).

As far as obesity is concerned, an alternative to body mass index (BMI) might be the measurement

of waist circumference, which appears to be associated with the risk of death (95).

In view of the potential of drugs to affect the occurrence of CV risk factors, more frequent

assessments may be required in certain situations, e.g glucocorticoids therapy (30, 34, 52, 92, 96).

Recommendation # 3: Other comorbidities

1. Osteoporosis .

All SLE patients

should be assessed for adequate calcium and Vitamin D intake, regular exercise, and

smoking habit,4

should be screened and followed for osteoporosis according to existing guidelines

o for postmenopausal women

o for patients on glucocorticoids, or on any other medication that may reduce

BMD

2. Cancer . Cancer screening is recommended according to the guidelines for the general

population, including PAP smears..

SLE patients are at increased risk of comorbidities, among which osteoporosis and cancer have

been considered in the present recommendations due to their frequency (97-121).

In the majority of the studies included in our SLR, osteoporosis was assessed by DXA according to

WHO definitions. The prevalence of fractures, when evaluated, was done by radiographs. The

majority of data refer to women with SLE, either premenopausal or postmenopausal. The

prevalence of osteoporosis among SLE patients varied from 4 to 24% (spine 7-23%, femur 3-23%).

When only premenopausal patients were evaluated, the prevalence of osteoporosis ranged between

10-20%. Vertebral fractures had a prevalence ranging between 7.6% and 37% (98, 104,

110,114,117).

In SLE patients, additional risk factors for osteoporosis include treatment with glucocorticoids as

well as other medications that may impact bone mass (such as anticoagulant therapy or

immunosuppressive drugs) and by reduced levels of vitamin D related to the avoidance of sun

exposure or ethnicity (African, African- Caribbean, African- Americans) (97, 104, 105, 108, 113,

118, 119).

Osteoporosis is a well established side effect of chronic glucocorticoids use; although the incidence

of osteoporosis is time and dose dependent, there is no consensus about a ‘‘safe’’ dose. Indeed, data

suggest that bone loss is observed in patients exposed to 7.5 mg of prednisolone daily. According to

the EULAR- based recommendations on the management of systemic glucocorticoid therapy in

rheumatic diseases, “If a patient is started on prednisone >7.5 mg daily and continues on prednisone

5

for more than 3 months, calcium and vitamin D supplementation should be prescribed” (118).

Therefore, it is recommended that SLE patients be assessed for adequate calcium and Vitamin D

intake. In addition, assessment of modifiable risk factors for osteoporosis, such as smoking habits

and physical exercise are also recommended.

It is recommended that SLE patients should be screened according to the existing guidelines for

postmenopausal women (120, 121) and/or for patients treated with medications that may affect bone

mass (Table 1).

Table 1. Drugs that may affect bone mass

Glucocorticoids

Immunosuppressive drugs

- Cyclosporine

- Tacrolimus

- Methotrexate

Heparin

Thyroxine

Aromatase inhibitors

Longterm anticonvulsants (phenytoin, phenobarbital, carbamazepine, piramidone)

Gonadotropin releasing hormone antagonists

Proton pump inhibitors (omeprazole)

Loop diuretics

Antidepressants (particularly selective serotonin reuptake inhibitors- SSRIs)

The SLR found that cancer incidence is increased in SLE patients, particularly haematological

malignancies (non-Hodgkin lymphoma), cervical cancer (cervical intraepithelial neoplasm), breast

cancer and lung cancer (122-140).

6

In addition, an abnormal cervico-vaginal cytology is reported in up to 16% of examined patients,

with an OR ranging between 1.8 and 28 compared with the general population (Table 2) (135, 138-

140).

Table 2. Standardized incidence rate of cancer in SLE patients

Type of cancer Standardized incidence rate of cancer

All cancers 1.15- 1.59

Breast cancer 0.89- 2.1

Hematologic cancers

- Hodgkin lymphoma

- Non Hodgkin lymphoma

1.31- 2.75

- 2.4- 17.82

- 3.47- 11.63

Cervical cancer 3.08- 8.15

Lung cancer 1.31- 5.55

With the exception of cervical intraepithelial neoplasm, the existing studies fail to clearly show an

association between the development of cancer and treatment with immunosuppressive drugs (140).

No increased incidence of bladder cancer was reported, not even in association with

cyclophosphamide therapy, independent of the protocol (NIH protocol, Eurolupus protocol, or oral

administration) (141-143). The association between bladder cancer and cyclophoshamide use

described among patients with haematological malignancies and with vasculitis appears to be

related to the cumulative dose of cyclophosphamide and is significant for cumulative doses over 25

gr (144, 145).

Additionally, Bernatsky et al have found that SLE patients undergo cancer screening (mammogram,

fecal occult blood and PAP test) even less frequently than the general population (146).

Based on these data, it is recommended that patients with SLE undergo cancer screening at least

according to the guidelines for the general population (e.g, the American Cancer Society Guidelines

for the Early Detection of Cancer relative to breast cancer, cervical cancer and colon and rectal

7

cancer). However, taking in consideration the epidemiological and clinical characteristics of SLE

patients, the development of SLE specific guidelines might be considered.

As far as cervical intraepithelial neoplasm is concerned, literature data show that HPV (Human

Papillomavirus) DNA testing may improve the specificity of the diagnosis and therefore should be

considered (147-150).

Recommendation #4: Infection risk

# 4.1 Screening

We recommend that patients should be screened for:

Human Immunodeficiency virus (HIV) based on patient’s risk factors,

Hepatitis C virus (HCV), hepatitis B virus (HBV) based on patient’s risk factors,

particularly before immunosuppressive (IS) drugs including high dose glucocorticoids

are started,

Tuberculosis, according to local guidelines, especially before IS drugs including high

dose glucocorticoids are started,

Cytomegalovirus (CMV) testing should be considered during treatment in selected

patients.

# 4.2 Vaccination

SLE patients are at high risk of infections and prevention should be recommended. The

administration of inactivated vaccines (especially influenza and pneumococcus), following the

Centers for Disease Control (CDC) guidelines for immunosuppressed patients, should be strongly

considered in SLE patients on IS drugs, preferably administered when the SLE is inactive. For

other vaccinations, an individual risk/benefit analysis is recommended.

# 4.3 Monitoring

8

At follow up visits, continuous assessment of the risk of infection by taking into consideration the

presence of:

severe neutropenia (<500/mmc),

severe lymphopenia (<500/mmc),

low IgG (<500mg/dl).

Infection represents one leading cause of death in SLE patients and their occurrence has been

related both to immunosuppressive therapy and the disease itself (53, 151, 152).

The systematic literature review showed that SLE patients do not have an increased incidence for

HIV infection. Therefore, screening should be based on the patient’s risk factors.

Similarly, HBV and HCV infections do not have an increased incidence among SLE patients (156-

159). However, in view of the risks of occurrence and reactivation of the infection following IS

therapy, and with glucocorticoids in particular, we recommend that patients should be screened for

HCV and HBV infections before administering high dose glucocorticoids or any other IS

medications (160).

The majority of the studies of tuberculosis (TB) in SLE have been conducted in areas endemic for

the disease (161- 168). The frequency of TB among SLE patients is high in studies performed in

countries with endemic TB (2.5-13.8%) and low in studies performed in countries with a low

incidence of TB (0-1.4%). However, in general, the incidence of TB among SLE patients appears to

be higher than in the general population. In one study performed in Spain, TBC incidence was 6

fold higher than expected, in Hong Kong 5 to 15 fold higher, and in India 10 to 60 fold higher.

Routine TB testing in SLE patients is not recommended in non-endemic areas. However TB testing

before glucocorticoids and immunosuppressive drugs is recommended according to the CDC

recommendations (169).

9

In patients with SLE, anergy, particularly in association with glucocorticoids therapy, may occur

(170). Therefore, alternative screening methods (chest radiographs) should also be considered in

PPD negative patients.

Cytomegalovirus (CMV) is one of the most prevalent opportunistic infections in

immunocompromised patients (171- 173). Active CMV infection is defined as detectable viral

replication in peripheral blood or organs, or as a significant increase in CMV-specific antibodies.

CMV disease is defined as the clinical expression of active infections (fever, leucopoenia and

thrombocytopenia with or without specific organ dysfunction).

CMV antigenemia has been reported in 18 to 44% of patients and clinically evident CMV infection

in 0.5 to 0.6%. In patients treated with IV pulse MP in combination with IV pulse

cyclophosphamide, CMV antigenemia appears markedly higher. Taking into consideration that

CMV infection may mimic active SLE and might be frequent with high dose glucocorticoids

therapy used in the treatment of active SLE, we recommend that testing for CMV (antigenemia)

should be considered in selected cases, particularly patients with active disease undergoing therapy

with high dose glucocorticoids (173, 174).

In view of the morbidity and mortality associated with infections, SLE patients would greatly

benefit from vaccination programmes (175, 176). When considering vaccination in SLE patients,

aspects to be considered include (i) safety, (ii) possible impact on disease history and activity, and

(iii) effectiveness, i.e. ability to prevent infection and/or elicit protective antibodies.

Data available in the literature, from very small unconfirmed studies, suggest that vaccination may

be associated with the development of autoimmunity, which has raised concerns about its safety in

subjects with autoimmune diseases (177- 188). In addition, SLE flares have been described,

particularly after Hepatitis B vaccination. Some data appear to show that polyvaccines may be more

likely to be associated with the development of autoimmunity, as has repeated vaccination (183).

10

A number of studies are available in the literature showing that influenza vaccination is safe in

terms of side effects and of SLE flares (189-198). The majority of patients develop protective

antibodies, although some studies have shown a slightly reduced antibody production compared to

patients without SLE. Similarly, data suggest that vaccination against Pneumococcus is safe,

although a reduced anti-pneumococcal antibody production has been reported (189, 199-204).

Although this is most likely to occur in patients being treated with glucocorticoids and other

immunosuppressive agents.

Fewer data are available on the safety and efficacy of Hepatitis B vaccination. In 2007 Kuruma et al

reported on hepatitis B vaccination of 28 SLE patients with inactive SLE, treated with low dose

glucocorticoids and not receiving immunosuppressive medications, negative anti-dsDNA and anti-

cardiolipin antibodies. Patients were administered a recombinant vaccine. All patients developed

protective antibodies (26/28 after the 3rd dose and 2 after the 4th dose); no increase in SLE flares was

observed. The authors concluded that Hepatitis B vaccination might be safe in selected SLE patients

(205).

In 1998, Battafarano evaluated the safety of tetanus toxoid administration to SLE patients. No flares

of disease activity were observed, and 90% of patients developed protective levels of antibodies,

although a trend toward reduced response was observed in patients with active disease who were

receiving cyclophosphamide, azathioprine or prednisone > 10 mg/day (197).

It should be noticed that all these studies have evaluated the development of protective antibodies

but no data are available on the ability of these vaccines to prevent the occurrence of infection.

Inactivated live vaccines are contraindicated in patients taking immunosuppressive drugs and/or

glucocorticoids (at a dose > 20 mg/day), due to the risk of viral multiplication and monitoring the

risk of causing the disease (as with oral polio in the past).

Few studies have assessed whether leucopenia and low immunoglobulin levels are predictive of

infections in SLE patients. In a study of 82 SLE patients, Ng et al showed that a lymphocyte count

11

≤1x109/L was associated with an increased infection risk (OR 4.7). Low levels of IgG3 (≤ 60

µg/ml) or IgG4 (≤ 20 µg/ml) have also been associated with an increased risk of infections (206-

208).

Therefore, we recommend that the infection risk of SLE patients should be assessed, taking into

consideration neutropenia, lymphopenia, and IgG levels. In particular, total IgG and subclasses

levels should be assessed at least at the first patients assessment as well as at follow up visits in

patients taking immunosuppressive drugs.

Recommendation #5: Frequency of assessments

In the patient with no activity, no damage, and no comorbidity, we recommend assessments every 6

to 12 months. During these visits, preventive measures should be emphasized.

No data are available in the literature to suggest the optimal frequency of clinical and laboratory

assessment in SLE patients.

The assessment of patients with active disease should be related to the type of organ involvement,

the type of therapy and response (209).

The committee arbitrarily agreed on the need to assess patients with inactive disease, no organ

damage and no comorbidities every 6 to 12 months. During these evaluations, emphasis should be

given to the discussion of preventive measures such as sun avoidance, adequate vitamin D and

calcium intake, and weight control and other measures to reduce cardiovascular risk. Discussion

about quality of life, occupational problems as well as pregnancy planning could also be considered.

Patients in whom immunosuppression therapy is being reduced need to be monitored for

reactivation of disease especially those with previous renal disease which may recur without

symptoms (209-210).

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Recommendation #6: Laboratory assessment

#6.1 Laboratory assessment

We recommend monitoring of the following autoantibodies and complement:

At baseline: ANA, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, anti-phospholipid, C3,

C4.

Re-evaluation in previously negative patients:

o Anti-phospholipid antibodies: prior to pregnancy, surgery, transplant, and oestrogen

containing treatments, or in the presence of a new neurologic or vascular event.

o Anti-Ro and anti-La antibodies before pregnancy.

o Anti-dsDNA/ low C3 or C4 may support evidence of disease activity / remission.

#6.2 Other laboratory assessments

At 6-12 months intervals patients with inactive disease should have:

Complete blood count

Erythrocyte sedimentation rate

C reactive protein

Serum albumin

Serum creatinine (or eGFR)

Urinalysis and urine protein/creatinine ratio

If a patient is on a specific drug treatment, monitoring for that drug is required as well.

Autoantibody production is a key immunological feature of SLE. Antinuclear antibodies (ANA) are

found in more than 95% of the patients. Some autoantibodies may be involved in tissue injury.

Therefore, their determination may have prognostic value and may predict certain organ

involvement or disease flares (211- 273).

Since ANA and other autoantibodies are included in the ACR Classification Criteria, autoantibody

determination is part of the basic diagnostic evaluation of SLE patients.

13

Different studies have shown an association between anti-dsDNA antibodies and general disease

activity (sensitivity between 51-92%; specificity between 56 and 100%) and renal activity

(sensitivity ranges between 31.3 and 78.8%, specificity ranges between 25 and 97%), but other

studies have not. Few data are available on the association between anti-dsDNA and damage

development. As far as renal damage is concerned, one study reported a sensitivity of 60% for

doubling of serum creatinine. Another study reported a sensitivity and specificity of anti-dsDNA for

damage accrual (SLICC) of 64% and 50.5%, respectively (218- 241).

In 2002, Kavanaugh et published guidelines for anti-dsDNA antibody testing in SLE, showing that

anti-dsDNA antibodies correlate with overall activity of disease and with the presence and activity

of renal disease in patients with SLE, and they are useful monitoring disease activity (217). The

available data, however, do not support the indication of treating patients with anti-dsDNA

antibodies in the absence of clinical activity (serologically active/clinically inactive disease) (273).

Serum anti- Ro, anti- La and anti-RNP antibodies might be prognostic for the outcome of SLE in

general and of specific organ involvement. In particular, anti-Ro/SS-A and anti-La (SSB) antibodies

have been associated with the occurrence of neonatal lupus (241, 255, 260). These rarely change

over time and should be done at baseline and only repeated in pregnancy.

Anti-phospholipid antibodies (aPL) have been associated with general disease activity (sensitivity

range 13-63%; specificity range 59-77%), thrombotic manifestations (sensitivity for

thromboembolism 15%, specificity for thromboembolism 90%), damage development (OR of anti-

cardiolipin antibodies for damage at 5 years: 1.94 (CI =1.01-3.73), for severe damage at 5 years:

3.34 (CI =1.11-10.03), for increasing damage since diagnosis: 2.46 (CI =1.24-4.87). A recent SLR

has confirmed the association of aPL and pregnancy complications (miscarriages, still birth,

premature delivery, pre-eclampsia) (241- 262). The sensitivity and specificity of aPL for neurologic

damage ranged from 15 to 38% and from 84.3 to 98.4%, respectively. No data were available on the

sensitivity and specificity of aPL for transplant complications that may be related with the

14

occurrence of thromboembolism and few data are available on this aspect. Stone et al have

suggested a possible role of aPL in early graft loss among SLE patients undergoing kidney

transplant (263).

Complement levels are sometimes associated with active disease, although no predictive value for

the development of disease flares has been reported (213, 216, 270).

Severe anaemia has been variably associated with organ involvement (kidney), disease progression

(end stage renal disease) and prognosis (survival). Similarly, thrombocytopenia has been associated

with renal disease, disease progression to end-stage renal disease and prognosis (worse

outcome/survival) (241). Leucopoenia and lymphopenia have been associated with the occurrence

of infections (see also Recommendation 4) but only at very low levels.

Serum albumin, creatinine, urinalysis, urine protein/creatinine ratio and blood pressure provide

information on the presence and prognosis of renal involvement (271- 285).

Erythrocyte sedimentation rate (ESR) is a test widely used to monitor inflammatory rheumatic

diseases. However, in SLE, the predictive value of this test for disease activity is controversial.

Some authors found a strong positive correlation between ESR and disease activity, while others

have failed to observe any correlation. Vilá L.M. et al, in the LUMINA multiethnic cohort, reported

a strong and independent association between ESR level and SLAM and physician global

assessment (PGA) at enrolment and for all visits of the study (286). Mirzayan M.J. et al, in a

prospective study on 120 Caucasian SLE patients, observed a significant predictive value of ESR

for disease flares in the subsequent year (defined as an increase of at least 3 points in the SLEDAI

score; p=0.001) but not for SLEDAI at enrolment, after 1 year and after 2 years (287). On the other

hand, Esdaile JM et al, in a longitudinal prospective observation, concluded that there is no

evidence that changes in ESR values are able to predict future flares (216).

C reactive protein (CRP) is an acute–phase reactant whose concentration may increase with tissue

inflammation or necrosis, infections, and malignancy. CRP levels are routinely used in monitoring

15

disease activity and response to treatment in several rheumatologic conditions such as rheumatoid

arthritis, spondyloarthropaties, or vasculitis. Controversial results have been reported on the

significance of CRP in SLE patients. Many authors reported that SLE patients rarely have elevated

CRP levels and in case of a significant increase in this parameter, a superimposed infection should

be excluded. More recently, some studies have shown an association between disease activity and

CRP values, while other studies CRP levels have failed to distinguish active from inactive patients.

An increase of CRP in one study does correlate with the presence of Jaccoud’s arthropathy (288-

291).

In summary, the clinical utility of CRP and ESR determination to assess disease activity in SLE

patients is unclear, as these tests are nonspecific and many confounding factors may interfere with

results. On the other hand, they are relatively low cost and rapidly available, and CRP may be

useful to detect an infectious complication (fever or other clinical suspicion), especially in the

presence of very high values (> 50 mg/l).

Recommendation #7: Mucocutaneous involvement

Mucocutaneous lesions should be characterized, according to the existing classification systems, as

to whether they may be:

- Lupus erythematosus (LE)-specific.

- LE-nonspecific.

- LE mimickers.

- Drug-related.

Lesions should be assessed for activity and damage, using validated indices (i.e. CLASI).

Cutaneous manifestations occur often during the course of the disease, being observed in over 80%

of patients. They include LE-specific and LE-nonspecific skin lesions, primarily based on

histopathologic criteria (292- 303). The LE-specific cutaneous findings encompass the various

subtypes of cutaneous lupus erythematosus (CLE), which are subdivided into four different

16

categories as defined by constellations of clinical features, histological changes, laboratory

abnormalities, and average duration of skin lesions: acute CLE (ACLE), subacute CLE (SCLE),

chronic CLE (CCLE), and intermittent CLE (ICLE). In contrast, skin lesions, such as urticarial

vasculitis and livedo reticularis, are some of the most common LE-nonspecific cutaneous lesions

and are mostly associated with SLE.

However, the diagnosis of cutaneous manifestations in LE may be difficult, as many conditions may

mimic LE (Table 3) and therefore the diagnosis may require evaluation by an experienced

dermatologist and a skin biopsy for histological analysis.

Data from the Cutaneous Lupus Disease Area and Severity index (CLASI) study confirm this

difficulty, showing the presence of misdiagnosis among specialists (specificity of diagnosis of 0.46

for the rheumatology group versus 0.74 for the dermatology group). In addition, three out of the 11

patients enrolled in the first CLASI were excluded because findings from repeated biopsies showed

the presence of confounding conditions that made the diagnosis of CLE impossible (304- 306).

Follow-up re-biopsy is recommended if there is a change in the clinical morphology of the lesions

or if there is a lack of response to treatment.

The CLASI index has been recently developed to assess patients with CLE. The index has two

scores, one describing activity of the disease and the second damage; the index has been validated

and its reliability has been shown. Recent data have confirmed its reliability when used by

dermatologists and also by rheumatologists. Although this index was developed to create a measure

of consensus in trials of CLE, its use in clinical practice might be considered at least in SLE patients

with prevalent cutaneous manifestations, as this might improve the quality of the physician

judgment on activity and response to therapy (304-305).

Table 3. Most frequent lupus mimickers

Subtype LE mimickers

17

ACLE Localized form:Dermatomyositis, rosacea, seborrhea, eczema , tinea facei, erysipelas, perioral dermatitis

Generalized form:Virus exanthema, drug eruption, erythema multiforme, toxic epidermal necrolysis, dermatomyositis

SCLE Tinea corporis, psoriasis, mycosis fungoides, erythema multiforme/toxic epidermal necrolysis, erythema annulare centrifugum, erythema gyratum repens, drug eruption, nummular eczema, seborrhea, eczema, actinic keratosis

DLE Tinea faciei, actinic keratosis, lupus vulgaris, sarcoidosis

LEP Different forms of panniculitis, subcutaneous sarcoidosis, polyarteritis nodosa, malignant lymphoma (in particular subcutaneous panniculitic-like T-cell lymphoma), morphea profunda, subcutaneouss granuloma anulare

CHLE Pernio, lupus pernio, vasculitis/vasculopathy

LET Lymphocytic infiltration of Jessner-Kanof, polymorphic light eruption, pseudolymphoma, B-cell lymphoma, plaque-like cutaneous mucinosis, solar urticaria

ACLE, acute cutaneous lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; LEP, lupus erythematosus profundus/panniculitis; CHLE, chilblain lupus erythematosus; LET, lupus erythematosus tumidus

Recommendation #8: Kidney

- Patients with a persistently abnormal urinalysis or raised serum creatinine should have urine

protein/creatinine ratio (or 24 h proteinuria), urine microscopy, renal ultrasound and be

considered for referral for biopsy.

- Patients with established nephropathy should have protein/creatinine ratio (or 24 h proteinuria)

and immunological tests (C3, C4, anti-dsDNA), urinary sediment microscopy and blood

pressure at least every 3 months for the first 2-3 years.

- Patients with established chronic renal disease (eGFR < 60 ml or stable proteinuria > 0.5

mg/24 hrs) should be followed according to the National Kidney Foundation guidelines for

chronic kidney disease.

Kidney involvement is common in SLE patients and is an important cause of morbidity and

mortality. Despite all therapies, up to 25% of patients treated with cyclophosphamide (CYC)

protocols may develop renal insufficiency and end stage renal disease (ESRD). Treatment

discontinuation is associated with the occurrence of flares - up to 50% - independent of the type of

treatment protocol used (307- 312).

18

The SLR found that serum creatinine, urine sediment analysis, proteinuria (either as 24 hours

proteinuria or urine protein/creatinine ratio) and blood pressure have a predictive value for the

presence and outcome of kidney involvement and the occurrence of flares. Urinary infection should

be excluded in presence of abnormal microscopy (270-285, 307- 317).

According to recently published Recommendations, renal biopsy has a role in diagnosing lupus

nephritis as well as defining prognosis and treatment and should therefore be considered (241).

Serum creatinine, urine sediment analysis, proteinuria and blood pressure have a predictive value

for the presence and outcome of kidney involvement and the occurrence of flares. Relapses of

kidney disease are common, being observed in up to 45%. The SLR found that the relapse rate

increases over time, being 6-9% at 1 year, around 24% at 2 years, 21-28% at three years and 25-

45% at 5 years. At 10 years, relapse rate is 45%. The estimate flare rate is 0.1-0.2 flares per patient

and year (284, 308-314).

The renal outcome has been variably defined as doubling serum creatinine or reaching end stage

renal disease (ESRD). The risk of doubling serum creatinine ranges between 7.4 and 8.5% at 5

years and between 14.3 and 18.2% at 10 years. The risk of developing ESRD ranges between 3 and

36%. The percentage of patients without ESRD ranges between 66 and 97%. Black patients have a

higher risk of developing ESRD (52% at 5 years). The following variables have been associated

with renal survival at 5 years: age (< 30=79%; >30=48%), ethnicity (Black= 49-59%, Others= 76-

82%), serum creatinine (<2.4= 79%, >2.4=31% or <2= 80%, >2=49%), hypertension (present=

69%, absent=87%), C3 complement, nephritic flares, kidney biopsy, activity index, and chronicity

index. Reduction of proteinuria after six months combination IS/stetroid therapy, i.e. renal response

is associated with a lower risk of doubling serum creatinine or ESRD (275- 280, 284, 285, 317).

Guidelines have been published for the monitoring of patients with chronic kidney disease

(http://www.kidney.org).

19

Recommendation #9: Neuropsychiatric manifestations

- SLE patients should be monitored for the presence of neuropsychological symptoms (seizures,

paresthesiae, numbness, weakness, headache, epilepsy, depression, etc) by focused history.

- Cognitive impairment may be assessed by evaluating attention, concentration, word finding and

memory difficulties (i.e. by asking the patient about problems with multitasking, with household

tasks, or memory). If there is a suspicion of any cognitive impairment, then the patient should be

assessed in further detail.

Neurological involvement (central, peripheral, or autonomic) occurs frequently in SLE. A wide

range of prevalence from 14 to 80 % has been reported in the literature (318- 326). The most

frequent syndromes observed are headache, mood disorders, seizures, cognitive impairement (CI)

and cerebrovascular disease.

The assessment of neurological symptoms is difficult and no specific instrument has been evaluated

in clinical practice. Therefore it has been suggested that patients should be monitored by clinical

history and examination.

As far as CI is considered, the tests evaluating CI in SLE are various and differ between studies.

The majority of studies report a high prevalence of CI; 7 out of the 30 studies examined reported a

very high prevalence (>50% of all patients evaluated), 8 studies reported a prevalence ranging

between 20 and 50%, and 6 a low prevalence (< 20%) with CI. In few studies, a comparison with

control groups was performed, either with patients with rheumatoid arthritis or with the general

population. In four studies, CI in control groups was much less prevalent than in SLE.

20

CI may be assessed by evaluating memory, attention, concentration, and word finding difficulties

(i.e. by asking the patient whether he can multitask, or whether she has difficulties with household

tasks, or whether he is forgetting things) (321- 326).

Recommendation #10: Eye assessment

In patients treated with glucocorticoids or antimalarials, a baseline eye examination is

recommended according to standard guidelines.

An eye examination during follow up is recommended:

in selected patients taking glucocorticoids (high risk of glaucoma or cataracts),

in patients on antimalarial drugs and

o low risk -> no further testing is required until 5 years after baseline; after the first 5

years of treatment, eye assessment is recommended yearly,

o high risk -> eye assessment is recommended yearly.

The incidence of retinopathy among SLE patients treated with antimalarial drugs is relatively low.

In a recent study of 400 patients with rheumatoid arthritis (RA) and SLE treated for more than 6

years, the prevalence of retinopathy was 0.5% (328- 331).

Risk factors for the development of retinopathy are age (above 60 years), presence of macular

degeneration, retinal dystrophy, obesity, liver disease, renal insufficiency, duration of therapy > 5

years, daily dose of hydroxychloroquine above 6.5 mg/kg, or chloroquine above 3 mg/kg. Few

cases are observed among patients treated for less than 5 years and with daily dose of

hydroxychloroquine of less than 6.5 mg/kg, or of chloroquine of less than 3 mg/kg (332- 334).

In 2002, recommendations on screening for chloroquine and hydroxychloroquine retinopathy were

published which included the need for a baseline eye assessment before starting therapy. Thereafter,

in low risk patients, no further testing is required for the next 5 years; after the first 5 years of

21

treatment, eye assessment is recommended yearly. In high-risk patients, an eye assessment is

recommended yearly (332- 335). According with published Recommendations, the baseline

examination should include a complete ophthalmologic examination including best-correcter

viasual acuity and dilated examination of the cornea and retina, a baseline field testing (Amsler grid

or Humphrey 10-2 field).

Glucocorticoids-induced cataracts occur among patients treated with glucocorticoids; some studies

suggest that 10-15 mg of prednisone daily for a year may be sufficient to cause cataracts. Data

available on SLE patients confirm a significant association between cumulative prednisone dose

(36.5 g) and development of cataracts with a RR: 1.9 (CI 1.4-2.5) (336- 337).

The EULAR evidence-based recommendations on the management of systemic glucocorticoid

therapy in rheumatic diseases indicate cataract or glaucoma as comorbidities based on a level of

evidence of IV (expert committee reports/opinions and/or clinical opinion of respected authorities)

and a strength of recommendation of 92 (CI: 87-96) (118, 339).

Systemic glucocorticoids increase the risk of glaucoma by raising the intraocular pressure. Authors

have reported the development of glaucoma in 19% of subjects with rheumatic diseases treated with

> 7.5 mg/day of prednisone vs 3% of those treated with 7.5 mg/day. In the general population, 18-

36% of those exposed to glucocorticoids had an increase in intraocular pressure. Risk factors for

glaucoma development are family history of glaucoma, age (over 40 years), ethnic background

(African-Americans are six to eight times more likely to develop glaucoma than are Caucasians),

diabetes mellitus, hypertension, hypothyroidism, great myopia, pre-existing glaucoma, chronic

uveitis, and iritis.

In addition eye assessment is required if there are symptoms suggesting eye involvement by lupus.

Eye assessment could be performed by an optician in countries were opticians are trained in

recognizing complex eye disease.

22

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