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J Indian Rheumatol Assoc 2002 : 10 : 80 - 96
INDIAN GUIDELINES ON THE MANAGEMENT OF SLE
A Kumar
Introduction
tions. Late mortality i.e. 10 years after diagnosis, on the other Systemic lupus erythematosus (SLE) is the prototype hand, is mainly attributed to atherosclerotic vascular disease9.
of systemic autoimmune diseases. The aetiology is not known There is a fair amount of iatrogenic morbidity and mortality.
as yet and the pathogenesis is complex, involving immuno-logical, genetic, hormonal and environmental factors. Dam- Indian guidelines on SLE: Why and for whom?
age to tissues and cells results from pathogenic autoantibod- Since SLE is a rare disease, a general physician is ies and immune complexes. It affects predominantly women not likely to be familiar with the complexities of its presenta- in their reproductive years. The median age of onset in Indian tion and the therapeutic challenges and dilemmas it can pose.
SLE is 24.5 years and the sex ratio (F:M) is 11:11. Remissions It is a disease, which primary care physicians would find dif- and relapses characterize the disease. The clinical manifesta- ficult to manage without the help of a specialist. Firstly, they tions and their severity in individual patients may vary con- should be able to recognize the possibility of this disease siderably and, therefore, the treatment strategy needs to be among patients in their practice. An early referral to the spe- cialist is desirable for improving the outcome. Once the diag-nosis is established and appropriate treatment instituted by a Incidence and prevalence
specialist, the patient can follow up with a primary care phy- SLE is rare in India. A prevalence study in India (car- sician provided the disease is mild and stable. All other pa- ried out in a rural population near Delhi) found a point preva- tients with SLE require periodic clinical reviews by a special- lence of 3 per 100,0002. This is a much lower figure than re- ist. A family physician can certainly collaborate with the spe- ported from the west (varying from 12.5 per100,000 adults in cialist in monitoring disease activity and treating patients with England3 to 39 per 100,000 in Finland4 and 124 per 100,000 moderate or severe disease. These guidelines have been for- in USA5). However, a fair number of cases of SLE are en- mulated to improve the quality of care for SLE patients. It is countered in any large hospital in India. Copcord Bhigwan hoped that the prognosis of Indian patients with SLE will im- study ( an ongoing, prospective population study from Pune) prove significantly with better awareness of diagnosis and treat- found a crude incidence rate of 1 per 25,000 person years i.e.
4 per 100,000 population per year (personal communication).
Despite its rarity, SLE has considerable impact on the patient, Clinical features of SLE in India
her/his family and health services available.
Clinical features reported by workers from different parts of India show some interesting regional variations10-15 General outlook of the disease
and these are brought out in Tables 1-3. It is evident that oral The prognosis of SLE is quite grim with more than ulcers are seen in about one-half of patients at presentation in half of the patients developing irreversible organ damage over those from eastern India as against about 10% from other parts.
time. Although the survival has improved in the west with Raynaud’s phenomenon is conspicuous by its absence in pa- modern treatment to the tune of 80% at 10 years after diagno- tients from southern India where lymphadenopathy tends to sis6, the Indian figures are not so good (50%-60% survival at be a presenting feature more often. Low frequency of neurop- 10 years)7,8. Possible reasons for poor survival in Indian SLE sychiatric manifestations at onset in northern India emerges include delay in diagnosis, referral bias (only the most serious as another significant difference. When patients are followed cases are referred by practitioners), suboptimal health care up for several years, significant differences can still be made facilities and an inherently more severe disease (genetic fac- out. These include lower frequency of photosensitivity and tors?) and endemic tuberculosis to which the lupus patients neuropsychiatric manifestations in western India, lower fre- are more susceptible. The major causes of death in the first quency of nephritis in central India and the rarity of Raynaud’s few years after diagnosis include disease activity and infec- in southern India in comparison to other parts of the country.
Indian Guidelines on the Management of SLE Table 1 Percentage frequency of presenting clinical features in patients with SLE from different regions in India
NA = not available, * = the 4 commonest presenting features (exact figures NA) Table 2 Cumulative percentage frequency of clinical manifestations in patients with SLE from different regions in India
Table 3 Frequency of laboratory abnormalities in Indian SLE
Diagnosis of SLE
Serology in SLE
The American College of Rheumatology has a Since SLE is associated with a number of autoanti- criteria for the classification of patients as having SLE16 (Table bodies, it is important to understand their relevance in clinical 4). If a patient has, at any time in his or her medical history, 4 practice. Some of these are useful as diagnostic markers, oth- of the 11 criteria documented, the diagnosis of SLE can be ers help in quantifying disease activity and still others are pri- made with about 95% specificity and 85% sensitivity. These marily of research interest, making no contribution to patient criteria are actually meant for epidemiological purposes (to ensure that SLE patients reported in the literature do in fact 1. Antinuclear antibody (ANA):
have the disease) and not for bedside diagnosis of an indi- ANA is a good screening test for SLE because 95% vidual patient. The diagnosis of SLE is based on clinical judge- of cases show a high titre (1:80 or more) of this autoantibody.
ment. SLE can be suspected whenever 2 or more organ sys- A negative test result makes the diagnosis highly improbable.
tems listed in Table 4 are involved. Thus, a lady with nephri- ANA may be positive in other rheumatic disorders such as tis and presence of ANA and anti-dSDNA meets only 3 crite- systemic sclerosis, Sjogren’s syndrome, overlap syndrome, antiphospholipid syndrome, polymyositis and rheumatoid ar- Indian Guidelines on the Management of SLE Table 4 Revised ACR classification criteria for SLE (1997 update)16
Fixed erythema, flat or raised, over the malar eminences, sparing nasolabial folds Erythematous, raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring Skin rash as a result of unusual reaction to sunlight by history or on physical exam.
Oral or nasopharyngeal ulceration, usually painless, observed by physician Involving 2 or more peripheral joints, characterized by tenderness, swelling or effusion a.Pleuritis- convincing h/o pleuritic pain or rub or pleural effusion on physical examination ORb.Pericarditis- documented by ECG, rub or e/o effusion a. Persistent proteinuria > 0.5 gm/day or > +++, ORb. Cellular casts- may be red cell, Hb, granular, tubular or mixed Neurological disorder a. Seizures- in the absence of offending drugs, or known metabolic derangement, e.g. uraemia, ketoacidosis or electrolyte imbalance, OR b. Psychosis- in the absence of offending drugs, or known metabolic derangement, e.g. uraemia, a. Haemolytic anaemia with reticulocytosis, OR b. Leukopaenia < 4000/cu mm on 2 or more occasions, ORc. Lymphocytopenia < 1500 on 2 or more occasions, ORd. Thrombocytopenia < 100,000/cu mm in the absence of offending drugs a. Anti-DNA: antibody to native DNA in abnormal titre, OR b. Anti-Sm: presence of antibody to Sm nuclear antigen, ORc. Positive finding of aPL antibodies based on: 1) ↑ serum level of IgG or IgM aCL or 2) a positive test result for lupus anticoagulant, using a standard method, or 3) a false-positive test for syphilis forat least 6 months and confirmed by TPI or FTA-abs test An abnormal titre of ANA by immunofluorescence or an equivalent assay at any point in time in the thritis. Like the rheumatoid factor test, ANA may also be posi- SLE. Also, performing serial titres of ANA in a diagnosed tive in chronic infections, malignancies and in normal indi- case of SLE is of no clinical value because it does not corre- viduals. Thus, the specificity of ANA for diagnosis of SLE is late well with disease activity. It can remain positive for long periods in the absence of any disease activity. What we treat Although many laboratories use ELISA technique for the sake of convenience and economy, the gold standard ANAs are actually a family of autoantibodies, which method for testing and reporting ANA is the indirect immun- may be directed against any one of the following nuclear anti- ofluorescence method. The preferred substrate is a dividing cell line such as ‘HEp-2’, with rat liver sections as the next choice. Different types of staining patterns can be identified by this method such as homogeneous (diffuse), speckled (fine, coarse), rim (peripheral) and nucleolar. The staining patterns have been associated with different sub-types of clinical mani- Antibodies to the above subspecificities are also use- festations of lupus, though validated data are not published as ful in some situations and are discussed below: Anti-double stranded DNA antibody (anti-dsDNA): This
It is important to stress that the diagnosis of SLE must test has high specificity for SLE. However, the technique must be strongly suspected at the clinical evaluation before request- ensure absence of any contamination with single stranded DNA ing for ANA test. A positive result supports the diagnosis of in the antigen used. Farr assay (radioimmunoassay) and Crithidia lucilae method are very good in this regard but they are cumbersome and hence not very popular with most labo- ratories. Newer methods such as ELISA and haemagglutination have become available and are reasonable alternatives. The positivity of anti-dsDNA in SLE at the time of presentation is Laboratory investigations to be requested:
in the range of 60% (although the cumulative positivity dur- Although investigation plan for a case of SLE will ing the course of disease may approach 90%). Hence, anti-ds depend on the clinical picture, the minimum laboratory work- DNA can not be a good screening test for SLE. When posi- tive, the test establishes the diagnosis of SLE. The anti-dsDNAtitres most often correlate with disease activity.
1. Haemoglobin, WBC, Differential count, ESR2. Urine routine (preferably a fresh sample examined) and Antibodies to extractable nuclear antigens (anti-ENA):
microscopy, and 24 hour protein and creatinine These include anti-Sm, anti-UIRNP, anti-Ro and anti-La anti- bodies. Anti-ENA are found only in about 50% of sera which 3. Serum chemistry (urea, creatinine, liver function tests, are positive for ANA. High titres of anti-UIRNP are associ- ated with mixed connective tissue disease (MCTD) which is a subset of SLE with prominent Raynaud’s phenomenon, scle- rodactyly, proximal myopathy and mild or no renal involve-ment. Anti-Sm antibody is quite specific for SLE but it is found Additional investigations can be obtained depending only in 10-30% of patients. Anti-Ro is associated with ANA on the clinical indications and these are mentioned at appro- negative SLE, Sjogren’s syndrome, congenital heart block, neonatal SLE and subacute cutaneous lupus erythematosus.
Anti-La is associated with SLE and Sjogren’s syndrome. Anti- Referral to Rheumatologist/Specialist:
histone antibodies are associated with drug-induced SLE.
Referral to a rheumatologist is indicated for the fol- Anticardiolipin antibodies (aCL) and lupus anticoagulant:
This is discussed under ‘Antiphospholipid syndrome’ (please 2. Periodic evaluation of disease activity and severity 3. Management: general plan of treatment, patient education, management of uncontrolled/serious, life Complement levels (C3 and C4): These two complement
threatening disease, prevention and treatment of components are useful in the diagnosis and follow up of SLE.
Their levels drop because of consumption. C3 and C4 levels 4. Special situations such as pregnancy, antiphospholipid are negatively correlated with lupus activity. syndrome, concomitant infection and surgery Evaluation of disease activity and severity
Differential diagnosis of SLE: The following conditions need
A number of validated indices are available for quan- to be considered in differential diagnosis of SLE- tifying disease activity. The more popular indices include-BILAG17, SLEDAI18, SLAM19 and LAI.20 These help in for- Undifferentiated connective tissue disease mulating the overall treatment plan and assessment of prog- nosis. Table 5 shows the details of scoring used in SLEDAI.
A valid measure of damage in patients with lupus is the SLICC/ Indian Guidelines on the Management of SLE Table 5 SLE Disease Activity Index (SLEDAI)
Recent onset, exclude metabolic, infectious or drug causes Altered ability to function in normal activity due to severe disturbance in the perception of reality. Include hallucinations, incoherence, markedly loose associations, impoverishedthought content, markedly illogical thinking, bizarre, disorganised or catatonic behaviour.
Exclude uraemia and drug causes Altered mental function with impaired orientation, memory or other intellectual function, with rapid onset and fluctuating clinical features, 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. Excludemetabolic, drug or infectious causes Retinal changes of SLE. Include cytoid bodies, retinal haemorrhages, serous exudates/ haemorrhages in choroid or optic neuritis. Exclude hypertension, infection or drug causes Cranial nerve disorder New onset of sensory or motor neuropathy involving cranial nerves Severe persistent headache: may be migrainous, but must be non-responsive to narcotic New onset of CVA. Exclude atherosclerosis.
Ulceration, gangrene, tender finger nodules, periungual infarction, splinter haemorrhages, or biopsy or angiogram evidence of vasculitis > 2 joints with pain and signs of inflammation (tenderness, swelling or effusion) Proximal muscle aching/weakness, associated with elevated CPK/aldolase or EMG > 5 RBC/HPF. Exclude stone, infection or other causes Pleuritic chest pain with pleural rub/effusion/pleural thickening Pericardial pain with at least 1 of the following: rub, effusion or ECG or Echo Decrease in CH50, C3 or C4 below the normal limit of Lab Management
control with safe and established medications. Most marriedwomen in India are housewives, and with active systemic lu- Patient Education
pus erythematosus their emotional stress worsens if the In order to obtain optimal results from drug therapy, husband’s moral support is inadequate or the in-laws have patient education plays a vital role and must be paid due at- unrealistic expectations from the patient whose functional sta- tus may be significantly compromised due to the symptoms,dominantly fatigue and polyarthralgias. The physician can play How to educate the patient about the disease? a vital role in counselling the family members thereby facili- Every newly diagnosed patient needs to be educated tating the process of obtaining the much needed support from about the disease. In this regard, pamphlets especially written them. It has to be emphasized that the disease is eminently for patients can be very helpful. For illiterate patients, the treat- controllable with appropriate treatment and patients can en- ing physician or a specialist nurse will have to spend the nec- joy long periods of remission and have happy and successful essary time on education. It is often useful to offer a new pa- tient the opportunity to interact with other previously diag-nosed lupus patients who are identified by the specialist as having a positive outlook of the disease and the enthusiasm to Sunlight is generally detrimental to the health of lu- function as a counsellors. In many advanced centres (outside pus patients and frequently responsible for exacerbations of India), community-based lupus support groups exist and they lupus activity. Photosensitive patients must be advised to wear perform this vital function. The biological behaviour of the protective clothing with long sleeves etc, use sunscreens disease, in particular, the long remitting and relapsing course (creams/lotions) with sun- protection factor (spf) of more than of the disease must be explained to the patient. The need for 15 and to avoid going outdoors during daytime when sunlight long-term treatment and careful monitoring of various param- is intense (if absolutely necessary, they must use an umbrella eters must be emphasized. Some useful web-sites for lupus to screen off sun). Sun rays reflected from sea water around patients include www.lupus.org/lupus, www.livingwithlu sunrise and sunset are also harmful. Office-workers should pus.com and www.patient.co.uk/illness/l/lupus.htm Patients avoid sunlight from windows and even exposure to overhead also need advice regarding marriage, contraception, pregnancy fluorescent lights. The ultraviolet rays, in particular, have to and brest-feeding. As regards marriage, the physician should be avoided, and hence the unprotected exposure to low pollu- discuss the risks involved openly with the patient. Participa- tion areas such as seashores and hill stations frequently pre- tion of the fiancee is crucial. The patient must be encouraged cipitate relapse of lupus activity. Computer screens can also to take other important participants also into confidence; oth- be a source of ultraviolet rays. Even photosensitizing drugs erwise marriage is not likely to succeed. The relapsing and (e.g. demeclocycline, sparfloxacin, dapsone, amiodarone etc.) remitting nature of the disease must be explained clearly.
However, it should be emphasised that fertility in lupus is notimpaired though abortions and foetal wastage occur frequently.
Normal outcome of pregnancy is possible with appropriate Infections are common in SLE and therefore, patients care. Contraception is essential during phases of active dis- must get any unexplained fever evaluated promptly. This is ease. Oral contraceptives with relatively small amounts of particularly necessary when patient is on long-term steroid/ oestrogens (< 35 µg) or pure progesterone preparations are cytotoxic therapy. Other situations such as renal failure, car- preferred. Alternatives include condom and diaphragm with diac valvular vegetations and ulcerative mucocutaneous le- spermicidal jelley. Intrauterine devices should be avoided sions also predispose SLE patients to infections. When lupus because of the increased risk of infections in lupus. Pregnancy patients present with fever of unknown origin the cause could and breast feeding are discussed under ‘Pregnancy in SLE’.
be an infection or lupus activity itself. A diagnostic dilemmamay present when work-up for infection is negative and there are no obvious leads. In this situation, elevated C-reactive Family support is vital in the management of SLE, protein levels in blood favour a diagnosis of infection. Lupus and the spouse or parents must be taken into confidence and activity is generally not accompanied by rise in CRP. Patients explained in detail about the disease. Explaining the disease undergoing splenectomy, must receive pneumococcal vaccine requires skill and maturity on the part of the physician and preferably before surgery. It is a good policy to give influenza should focus on a positive weighted overview and a realistic vaccine yearly and to institute antibiotic prophylaxis for all expectation of treatment that essentially is disease activity dental, genitourinary and other invasive procedures.
Indian Guidelines on the Management of SLE General approach to the drug therapy of SLE:
Since there is a range of severity of disease manifes- myocarditis, mesangioproliferative or minimal change lupus tations, proper categorization based on clinical and labora- nephritis, haemolytic anaemia and thrombocytopenia tory features is the first therapeutic step. The following scheme For moderate and severe manifestations, predniso- lone 1 mg/kg orally per day is the drug of choice. Antimalarialsmay be administered concomitantly. High dose of steroid must Category I (Mild SLE)
be continued till disease activity is well controlled that usu- Characterised by arthritis, arthralgia, myalgia, fatigue, ally takes up to 6 weeks when it should be tapered off slowly mild mucocutaneous involvement, low-grade fever, mild se- over 6 to12 months. In a toxic appearing patient, the adminis- tration of intravenous pulse methylprednisolone (15 mg/kg, Musculoskeletal complaints are the commonest fea- max. 1 g) over an hour for 3 or 5 consecutive days may achieve tures of SLE. For mild symptoms, NSAIDs and analgesics rapid control of lupus activity. Dexamethasone 100 mg is a may suffice. NSAIDs can occasionally cause adverse effects good, cheap and equally effective alternative steroid for pulse which may resemble those produced by the disease itself such therapy. Although rare, arrhythmias, accelerated hypertension, as proteinuria, edema, renal failure and aseptic meningitis.
psychosis, seizures and sudden death have been reported with In some patients, the above symptoms may not be pulse therapy. The pulses should be followed by oral pred- alleviated with NSAIDs alone, and they should be prescribed antimalarials (chloroquine, hydroxychloroquine). These drugs Calcium supplements (1 gm/day) and vitamin D (800 are particularly useful for cutaneous manifestations of SLE.
units/day) prescribed along with steroids retard osteoporosis.
These agents have multiple properties: immunosuppressive Alendronate 10 mg daily or 70 mg once a week is a good anti-inflammatory and sun-blocking. They are also reported antiresorptive drug for prevention of osteoporosis in patients to possess anti-platelet and cholesterol lowering effects. The starting on long-term steroid therapy.
drug of choice is hydroxychloroquine (200 mg BD for 3 A maintenance dose of oral steroid (beyond 6 months) months and then 200 mg daily). The maintenance dose must is not necessary in the majority of these patients and most not exceed 6 mg/kg/day. Although the incidence of retinal tox- often it is possible to maintain the remission with antimalarials icity is very low, annual monitoring of vision with perimetery and intermittent use of NSAIDs. INH prophylaxis in Indian using a red object is recommended (for chloroquine, 6-monthly patients has been a point of debate because of fear of promot- monitoring is desirable). The drug must be discontinued if a ing INH resistance. However, this risk is very low because of central scotoma is detected at any stage. Other significant side the small bacillary load present in this setting. One Indian study effects include nausea, pruritus, hyperpigmentation, myopa- on patients with SLE starting on steroids showed 82% protec- thy and rarely psychosis. Use of hydroxychloroquine during tion from tuberculosis with INH prophylaxis in one year.22 In pregnancy is controversial. When antimalarials are withdrawn the Indian context, it may be better to use 2-drug prophylaxis after prolonged administration, some patients may develop a (Rifampicin + INH or INH + Ethambutol) for a period of one relapse of lupus activity. In refractory cases, quinacrine may be combined with hydroxychloroquine. Alternatives includedapsone and thalidomide. Quinacrine and thalidomide are, Category III (Severe SLE)
Characterised by organ/life-threatening features such Patients not responding to the above measures may as focal/diffuse proliferative glomerulonephritis with or with- be treated with low-dose steroid therapy (Prednisolone 0.3- out azotaemia/hypertension, lupus cerebritis with recurrent 0.5 mg/kg/day) for 4-6 weeks followed by slow tapering. For seizures, acute confusional state, coma; systemic necrotizing lupus dermatitis, there is also a role of local steroids, includ- vasculitis such as one causing peripheral gangrene, GI bleed- ing topical creams and ointments and injections into unrespon- sive skin lesions. However, the steroid cream application for A combination therapy consisting of high-dose daily facial rash is not recommended. Adequate protection against oral prednisolone (40-60 mg/day) and intravenous cyclophos- phamide pulses (0.75 gm/m2, maximum of 1 g, over 1 hour) isrecommended. The cyclophosphamide pulses are given once Category II (Moderate SLE)
a month for 6 months by which time usually remission is Characterised by high-grade fever, toxaemia, severe achieved and then a maintenance pulse is administered every mucocutaneous manifestations, marked photosensitivity, mod- 3 months for a total of 2 years of cytotoxic therapy. Predniso- erate to severe serositis, lupus pneumonitis, mild to moderate lone is tapered off or reduced to a very low dose i.e. 5-7.5 mg nous lupus nephritis, chronic sclerosing lupus nephritis, sei- per day by 6 months. At least two-thirds of patients maintain zures without other evidence of lupus activity, behavioural a long-term remission after this treatment regimen.
disorders without other serious manifestations, resistant throm- Haemorrhagic cystitis is rare if attention is paid to adequate hydration after the pulse and prompt voiding of bladder and Immunosuppressive therapy does not play any sig- co-administration of MESNA. The overall risk of irreversible nificant role in these conditions. Treatment of antiphospholipid ovarian failure was noted to be 39% in one study. It was much higher for women aged more than 30. Infertility is common in If seizures or psychosis occur as isolated events with men as well and sperm banking is recommended, if facilities no evidence of lupus activity elsewhere in the body, only symp- are available. Bone marrow suppression and secondary infec- tomatic treatment is recommended. Steroids are not indicated.
tions (Herpes zoster, tuberculosis, pneumocystis carinii, sta- Pure membranous glomerulonephritis (WHO Class phylococcus, pseudomonas etc.), sclerosing cystitis and blad- V) may be treated initially with prednisolone 1 mg/kg/day. If der carcinoma, are the other adverse outcomes.
there is no response after 6 weeks (85-90% of cases), steroids Some authorities recommend the above regimen for may be quickly tapered off because they are not likely to help.
induction of remission (the first 6 months), which is then main- There is no proven role of cytotoxic drugs in the treatment of tained with azathioprine 2-2.5 mg/kg/day for about 2 years.
this condition in SLE. Renal failure occurs but is less frequent Alternatives include intravenous pulses of steroids on 3 con- as compared with proliferative glomerulonephritis. However, secutive days each month, daily oral administration of cyclo- transformation of pure membranous nephropathy to prolif- phosphamide (2 mg/kg/day) or azathioprine from the begin- erative nephropathy is well documented and can occur in about ning or a combination of these two agents along with oral one-third of patients in follow up.23 There must be awareness prednisolone. The latter is believed to be the most potent (and of this fact and repeated urine examination should be done so the most toxic) regimen. Cyclophosphamide based regimens that the transformation, when it occurs, is picked up and treated have been shown to be superior in achieving renal preserva- tion. Plasmapheresis, methotrexate, cyclosporine and Chronic sclerosing glomerulonephritis is best treated mycophenolate mofetil are other options.
with conservative therapy, dialysis and transplantation. Im- Progressive organ damage may still occur over sev- munosuppressive therapy is not beneficial. At least, 3 months eral years despite achieving good short-term remissions in of dialysis is recommended before considering renal trans- these patients. Although the overall incidence of end stage plant as the outcome of the transplant is better in patients whose renal disease (ESRD) is reduced, there is no firm evidence lupus disease activity remains clinically stable on dialysis for that patient survival is improved by double or triple drug regi- mens compared with steroid alone. This is because the out-look of ESRD is so much better now with the availability of For refractory thrombocytopenia, danazol may be dialysis and renal transplantation services. However, in India useful. Colchicine and vincristine are sometimes useful to where more than 90% of eligible ESRD candidates do not improve the platelet count. Splenectomy may be indicated in have access to maintenance dialysis or renal transplantation, some cases where platelet count tends to be less than 50,000/ combination therapy offers definite survival advantage.
cu mm and maintenance requirement for steroids is high. Such There are no definite protocols for lupus cerebritis patients should receive pneumococcal vaccine.
but cyclophosphamide pulses have been used in combination Plasmapheresis may be employed in refractory cases with oral high-dose steroids, as in the case of lupus nephritis.
where steroid and cyclophosph-amide pulses do not producesatisfactory results. Intravenous immunoglobulin has also been Category IV (SLE with miscellaneous features)
used in similar situations. A few instances of successful re- Characterised by antiphospholipid syndrome (recur- mission of refractory lupus following stem cell transplant are rent DVT, CVAs, recurrent foetal loss etc.), pure membra- Indian Guidelines on the Management of SLE SPECIFIC ISSUES IN THE MANAGEMENT OF SLE
NEUROPSYCHIATRIC LUPUS
e. Movement disorders – Chorea is characteristic and is
present in in up to 1% of patients. Hemiballismus and parkin-
Neuropsychiatric manifestations in SLE are an im- sonian like features are reported in fewer numbers.
portant cause of morbidity and even mortality. These can be f. Myelopathy- Transverse myelitis, is an acute illness with
the initial presenting symptoms or may come up subsequently symptoms of back pain, weakness or paralysis, bilateral sen- during the course of illness. The following entities have been sory deficits and loss of sphincter control which may progress recognized as features of nervous system manifestations of over hours to days. It occurs in approximately 1% of cases.
Diagnosis is made clinically and supported by CSF pleocyto-sis, elevated protein or reduced glucose level, and magnetic resonance studies showing focal cord edema. Antiphospholipid antibodies have been associated with this entity. Up to 25% of g. Seizures are amongst the commonest neurological mani-
festations (17-37%) and one of the features listed in ACR clas- sification criteria for SLE. Generalised, simple partial and par- tial complex seizures have been reported. The aetiology is multifactorial and secondary causes include metabolic de- rangement due to uraemia, hypertensive crisis and antiphospolipid antibodies. The presence of status epilepticus h. Acute confusional state –The ACR nomenclature and case
definitions for neuropsychiatric lupus syndromes suggest us- a. Aseptic meningitis – Features of meningeal irritation are
ing the term ‘acute confusional state’ for the entire spectrum present in up to 5% of patients. It is necessary to exclude pyo- of delirium to coma. Old term ‘organic brain syndrome’ has genic, fungal and tuberculous infection. The CSF shows an been dropped. It is present in 2-40% of cases and has a seri- increased protein, lymphocytosis and a reduced glucose con- ous prognostic significance. The two most frequent causes of tent. All of these findings are encountered with fungal and coma in SLE are stroke and acute confusional state.
tuberculous meningitis and the differentiation is frequently i. Cognitive dysfunction has been reported in 21-35% of
cases. This consists of difficulty in recall, calculation, con- b. Cerebrovascular disease – Stroke is seen in up to 15 % of
centration and word finding. The use of instruments like Mini cases. The causes of stroke include large and small vessel Mental State and the Neurobehavioural Cognitive Status Ex- thrombosis, intracerebral haemorrhage and subarachnoid amination is required to bring out this abnormaility. It may haemorrhage. Ischemic stroke is partly attributable to the pres- ence of circulating antiphospholipid antibodies and prema- j. Anxiety and mood disorder – This is commonly seen in
ture atherosclerosis. Large haemorrhage is less common and SLE but the cause is not clear. Reaction to the presence of a is due to aneurysmal rupture and active vasculitis. The occur- chronic illness or SLE primarily could be responsible.
rence of a cerebrovascular disease in patient with SLE ad- k. Psychosis - Occurs in up to 23% of cases. Presents as
parnoia and hallucinations (visual or auditory). Recovery is c. Demyelinating syndrome – It refers to relapsing myelopa-
complete but relapses are common. Distinction from corti- thy and optic neuropathy in patients with lupus. These were costeroid psychosis can be difficult.
earlier referred to as ‘lupoid sclerosis’ and reflect that mul- Some of the above manifestations are known to be associated tiple sclerosis and SLE share several clinical features.
with antiphospholipid antibodies, e.g. strokes, chorea, some d. Headaches- The frequency of headache in lupus is not par-
myelopathies and seizures. However, others such as cognitive ticularly increased. However, intractable headache or head- dysfunction, seizure, acute confusional state, psychosis, anxi- ache of recent origin could be due to stroke, encephalopathy, ety and depression, myelopathy, peripheral neuropathies and subdural haematoma, cerebral sinus thrombosis and aseptic headache are non-thrombotic disorders and could be due to meningitis. The earlier description of lupus headache as mi- antineuronal antibodies, antiribosomal P antibodies, immune- grainous has been refuted by recent studies.
complexes and vasculitis. Other important considerations areas follows: 1. Side effects of medications for the treatment of SLE – value suggest vascular insufficiency and in absence of Corticosteroid in particular can cause psychosis, euphoria and haemorrhage proved by an imaging study, anticoagulation is altered moods. Antimalarials can induce hyperirritability and seizures. NSAIDs are known to be associated with aseptic Treatment
In diffuse disease, such as acute confusional state, 2. CNS infections - Tuberculosis, bacterial endocarditis, her- evidence of active inflammation in the brain, such as increased pes simplex encephalitis, meningitis have been mistaken for cells and protein in the CSF, brain swelling on MRI or CT, or CNS lupus. A lumbar puncture for CSF fluid analysis is a psychosis is generally managed with prednisolone 1-2 mg/kg/ day administered orally. Those who are unresponsive to this 3. Fluid and electrolyte imbalance: Hypokalemia, hyponatre- dose of prednisolone may be administered IV methylpred- mia, water intoxication and syndrome of inappropriate antidi- nisolone 1000mg/day for 3 consecutive days. Pulse adminis- uretic hormone can induce psychosis.
tration of IV cyclophosphamide in a dose of 750 mg/m2 ev- Clinical and Laboratory evaluation:
ery 3-4 weeks may be tried in refractory cases. Focal disease a. Thorough history and detailed physical examination in- such as cerebral thrombosis, chorea and some cases of trans- cluding neurological and mental status evaluation.
verse myelitis where anticardiolipin antibodies may be asso- b. Baseline haematology, chemistry and immunological stud- ciated, is treated on the lines of APS (vide infra). Steroids are ies. The serology should include lupus anticoagulant, anticardiolipin antibodies. If facilities are available anti ribo- Other specific entities
somal P antibody levels and antineuronal antibodies may be Transverse myelitis : Requires aggressive treatment with
prednisolone orally 1.5 mg/kg/day and IV cyclophsophamide c. CT and MRI are indicated in cases of stroke, stupor/coma bolus. If there is no improvement, plasmapheresis should be and psychosis. MRI is more sensitive than CT in picking up haemorrhages, infarcts and oedema. CT is better for detecting Seizures: For generalized seizure, phenytoin and barbiturates
are used and for focal, carbamazepine, valproate or gabapentin d. CSF IgG index (CSF IgG / CSF albumin divided by serum IgG / serum albumin) is often a useful test to differentiate Headaches: Most patients respond to NSAIDs. In intractable
between cerebritis and vascular stroke as the cause of mental disequilibrium or confusional state or loss of conciousness.
Chorea: No specific therapy is required.
However, the normal index (usually around 0.5) must be es- Cranial /autonomic and peripheral neuropathy: Oral Pred-
tablished for the laboratory and if it is higher than the normal, nisolone in a dose of 1mg/kg/day is useful.
then cerebritis or vasculitis is the more likely cause necessi- Cognitive dysfunction: Consider reducing the dose of pred-
tating aggressive immunosuppression whereas a lower index nisolone. If associated with APS, anticoagulate.
Indian Guidelines on the Management of SLE LUPUS NEPHRITIS
Lupus nephritis is currently defined as the presence In the first 3 situations, the histology may be focal or of more than +++ or 0.5 gram/24 hr proteinuria or presence diffuse proliferative disease, membranous lupus, or, less of- of cellular casts of any type (Table 4). Using this definition, ten, thrombi associated with antiphospholipid antibodies. Each lupus nephritis occurs in about half of SLE patients (range: of these disorders may require a different form of therapy.
35%-73%) in India (Table 2). It is rare for lupus nephritis to Patients with acute renal insufficiency, active lupus serology, present with progressive renal insufficiency with repeatedly and an active sediment (red cells and red and white cell casts) normal urinalysis. Also, nephrotic range proteinuria is uncom- almost always have diffuse proliferative disease; these patients mon (app. 10%) in Indian lupus (Table 3). Thus, reliable urine do not need histologic confirmation if there is clear clinical examination is the single most important investigation for early diagnosis of lupus nephritis; clinical examination is generallyunhelpful. Renal tubular acidosis is known to occur more fre- Principles of treatment of lupus nephritis
General measures: It is advisable to restrict salt if Renal histology can be studied by light microscopy, hypertension is present, fat if hyperlipidemia or nephrotic syn- immunofluorescence and electron microscopy. The WHO clas- drome is present, protein should be restricted if azotaemia is sification scheme combines all 3 modalities (Table 6). Activ- present and calcium should be supplemented with steroid ity and Chronicity indices can be derived by the pathologist therapy. Meticulous control of hypertension is desirable. Preg- nancy should be avoided during active lupus nephritis with Table 6 : WHO Classification of lupus nephritis
suitable contraception (vide infra). NSAIDs should be avoided Patterns Immunofluorecence Electron Microscopy in the presence of impaired renal function.
Mesangial Peripheral Mesangial Subendothelial Subepithelial Immunosuppressive therapy: This is generally guided by the WHO Class of lupus nephritis.
If proteinura is > 1 gram/24 hours, anti- for 6-12 weeks, followed by tapering over 4. Class III & IV: Protocol for this group is already A high chronicity index correlates with poor renal Indications for kidney biopsy in SLE
outcome with progression to end stage renal disease despite 1. A patient with glomerular disease in whom the diagnosis treatment. High activity Index is also associated with poor outcome if not treated aggressively with appropriate immu- nosuppressive therapy. Patients with high chronicity index and 3. Nephrotic syndrome with a bland sediment serum creatinine more than 3 mg/dL should not be treated 4. A repeat biopsy may be performed for late progression of aggressively unless activity index is also high. If serum crea- the disease to distinguish between active lupus (which may tinine is chronically high and more than 5 mg/dL, aggressive require immunosuppressive therapy) and scarring of pre- immunosuppressive therapy is harmful. Such patients will be better managed with dialysis and transplantation in due course.
ANTIPHOSPHOLIPID SYNDROME
Antiphospholipid syndrome (APS) or Hughes syn- drome can present as a subset of SLE. More often, however, itoccurs as a primary condition.The hallmark of APS is throm- 1. aCL: Anticardiolipin IgG or IgM antibodies present at bosis (venous and/or arterial). The disease is characterised by moderate or high titres on 2 or more occasions at least 6weeks apart the presence of antiphospholipid antibodies (aPL) in the blood.
2. LAC: Lupus anticoagulant antibodies detected on 2 or Cross-sectional studies reveal 30% frequency of thrombosis A diagnosis of definite APS requires the presence of Clinical and laboratory features
Both arterial and venous thrombosis can occur in APS.
This contrasts with other prothrombotic conditions such as Treatment of APS
protein C, S or antithrombin III deficiency where only venous This can be considered under the following heads: thrombosis is seen. The common clinical manifestations of 1. Deep venous thrombosis: The main purpose of treatment APS comprise recurrent pregnancy loss, recurrent deep venous here is to prevent pulmonary embolism. Standard measures thrombosis and cerebrovascular accidents. Some patients de- include bed-rest, elevation of the affected limb to allow the velop the catastrophic APS in which thrombosis affects the oedema and tenderness to subside and anticoagulant therapy.
Heparin and warfarin should be started simultaneously so as blood vessels supplying vital organs simultaneously or in quick to allow an overlap of about 5 days. INR should be adjusted succession leading to a picture, which may mimic TTP or DIC.
between 3 and 4 on long-term warfarin therapy. The duration The prognosis of catastrophic APS is poor.
of warfarin therapy is life-long in patients with recurrent venous Antiphospholipid antibodies can be detected by 2 thrombosis. Thrombolytics such as streptokinase, urokinase methods: an anticardiolipin ELISA and a haematological test and tPA can be used but they are not more effective in pre- called lupus anticoagulant assay. Anticardiolipin antibody is venting pulmonary embolism. Thromboendarterectomy and usually of IgG class and this may exist alone or in combina- percutaneous insertion of IVC filter may be considered in spe- tion with IgM aCL. However, as many as 12% of patients may have only IgM aCL antibody. It is recommended that 2. Acute arterial thrombosis: In a patient with APS this usu- both IgG and IgM aCL should be tested in a suspected case of ally means a TIA or stroke, with MI and digital gangrene be- APS. Lupus anticoagulant is a less sensitive test but it is asso- ing less common. In some patients with acute stroke (< 3 hours ciated with the clinical syndrome of thrombosis more often duration), thrombolytics can be used but the standard of careis usually heparin followed by warfarin. Low-dose aspirin is than is aCL. A patient with APS may test positive for either or strongly recommended in patients who continue having throm- both LAC and aCL. Both tests should be carried out when botic events despite full anticoagulation. APS patients with acute MI can be treated with thrombolytics, angioplasty orcoronary stents. Peripheral arterial thrombosis can be treated Diagnosis (Consensus Classification Criteria)
with thrombolytics or heparin or angioplasty.
3. Catastrophic APS: These patients develop thrombosis in 1. Vascular thrombosis: One or more episodes of arterial, multiple organs and the features mimic DIC and TTP. Oral venous or small-vessel thrombosis, occurring within any contraceptives and other drugs, pregnancy, infection and sur- gical procedures have been identified as predisposing factors.
2. Complications of pregnancy: One or more unexplained Besides standard treatment, IVIG or plasmapheresis is rec- deaths of morphologically normal foetuses at > 10 weeks ommended in such patients. Still, prognosis remains poor.
of gestation, or One or more premature births of morpho- 4. Pregnancy (see next section)5. Thrombocytopenia: This is usually mild and does not re- logically normal neonates at < 34 weeks of gestation, or quire treatment. If the count tends to drop below 50,000/cu Three or more unexplained consecutive spontaneous abor- mm, treatment on the lines of ITP may be started.
Indian Guidelines on the Management of SLE PREGNANCY IN SLE
SLE does not impair the woman’s fertility except dur- ‘stress doses’ of steroids during delivery. Indications for Cae- ing periods of severe disease activity. However, there is in- sarian section include maternal reasons (avascular necrosis of creased risk of abortions (2-3 times), intrauterine growth re- the hips with inadequate hip abduction) or foetal reasons (foetal tardation and stillbirth. Pregnancy increases the risk of dis- distress, abnormal nonstress test, cephalo-pelvic dispropor- ease flare (40%-50% probability). The risk of flare is doubled tion and transverse presentation etc.).
in women who have active disease at the time of conception.
Lupus flares should be treated with the appropriate About 10% patients develop severe flares and therefore, lu- steroid dose. Cytotoxic drugs such as cyclophosphamide and pus pregnancy is rightly labled ‘high-risk’ pregnancy. With methotrexate should be avoided during first trimester except better understanding of lupus pregnancy, the outcome has in rare circumstances such as pulmonary alveolar haemorrhage improved considerably in the last 2 decades. Published data due to SLE. Azathioprine and cyclosporine can be used in on lupus pregnancy from India are scant.24,25 Both studies re- pregnancy with active SLE. More safety data are needed for ported poor foetal outcome in lupus pregnancy (40% and 58% respectively). Active disease at the time of conception corre- If antiphospholipid syndrome is present, there is lated with adverse foetal outcome. Laboratory monitoring greatly increased risk of thrombosis and foetal loss. Warfarin must be omitted as early as possible after conception (prefer- 1. Initial evaluation: Hb, WBC, DLC, platelets, urinalysis with ably the next day her first menses are missed and pregnancy microscopy, 24-hour urinary estimation of protein and creati- confirmed) and daily subcutaneous injections of low molecu- nine, blood urea, glucose and serum creatinine, serum lipids lar weight heparin (either enoxaparin 40 mg/day or dalteparin if patient is nephrotic or on steroids, Coombs’ test, aPL (IgG 5000 units per day) or low dose of heparin sodium along wih and IgM aCL, LAC), VDRL, anti-dsDNA, C3. Anti-Ro and low dose aspirin must be continued until delivery. The hep- anti-La should be done if there is a past history of giving birth arin is omitted 12 hours before delivery or cesarean section whereas low dose aspirin may continued. After post partum 2.Monthly laboratory assessment includes: Hb, WBC, DLC, bleeding stops, usually within a week after delivery, warfarin platelets, urinalysis (with 24-hr analysis if nephritis), chemis- is restarted. Corticosteroids are not recommended for APS try panel as above, anti-dsDNA and C3. Elevated anti-dsDNA alone because they increase maternal morbidity. In refractory and low C3 indicate active SLE or impending flare in over Foetal health should be monitored with repeated ul- 3.In case anaemia develops, peripheral smear should be re- trasound examinations, foetal heart monitoring and nonstress test. It is needless to emphasize that a neonatologist should be General principles of treatment of lupus pregnancy
available at the time of delivery. During the postpartum pe- It is strongly recommended that the disease should riod, the mother should be watched for infection and disease be in clinical remission for at least 6 months before the pa- exacerbation; both require aggressive treatment, when de- tient plans pregnancy. At the onset of pregnancy, a complete assessment of disease activity and severity should be made.
Breast-feeding is an important issue to be addressed The spouse and other family members should be counselled.
after successful pregnancy outcome. Majority of drugs are If disease is in remission, patient should be seen once every excreted in human milk in variable amounts. From neonatal month in the first half of pregnancy and more frequently, later perspective, maternal intake of prednisolone upto 30 mg/day, on. Laboratory evaluation should be performed as mentioned warfarin, cyclosporine in standard doses and weekly chloro- above. Blood pressure should be measured at every visit and quine for malaria prophylaxis are considered safe. If the dose more frequently in patients with nephritis. The prime focus of of prednisolone is greater than 30 mg/day, feeding should be the entire exercise of follow up should be early detection and avoided for 4 hours after ingestion of the morning dose of prompt treatment of lupus flare during pregnancy and the post- steroid. By this time the blood levels are quite low and very partum period. Presence of nephritis with or without hyper- limited amounts are secreted into the milk. However, breast- tension is an indication for low-dose daily aspirin from 10th feeding is contraindicated if mother is on cyclophosphamide, week till 36th week for prevention of pre-eclampsia. Patients azathioprine, hydroxychloroquine for SLE, salicylates, in- on long-term steroid therapy (> 2 years) are administered DRUG-INDUCED LUPUS (DIL)
Drugs can sometimes induce lupus-like disease and tis. Rash and renal involvement are rare. Laboratory profile associated autoantibodies. The incidence of DIL is estimated consists of ANA (antihistone type, usually IgG anti-H2A and at about 10% of idiopathic SLE. Numerous drugs have been H2B), leucopenia, thrombocytopenia, mild anaemia and raised incriminated or suspected. Those associated with moderate to ESR. Serolgical markers which are conspicuous by their ab- high risk include procainamide, hydrallazine and quinidine.
sence include anti-DSDNA, anti-Sm, anti-RNP, anti-Ro/La and Others such as INH, minocycline, d-penicillamine, methyl- hypocomplementaemia. Patients frequently do not satisfy dopa, captopril, chlorpromazine, carbamazepine and pheny- ACR criteria for classification of SLE. After withdrawal of toin are associated with a low risk.
the suspected agent, clinical improvement follows within days DIL typically develops several months to 3 years af- to weeks. However, autoantibodies may take several months ter continuous intake of the drug. Patients present with to disappear. Sometimes, NSAIDs and corticosteroids may arthralgias, myalgias, malaise, fever, serositis and polyarthri- be required for a short period to obtain symptomatic relief Indian Guidelines on the Management of SLE CHILDHOOD SYSTEMIC LUPUS ERYTHEMATOSUS
Salient features
the first few months of life. The cutaneous lesions may clear Childhood SLE is an autoimmune multisystem con- with the disappearance of maternal antibodies. Treatment is nective tissue disorder occurring in children below 16 years usually not required. Thrombocytopenia, haemolytic anaemia of age. It is the second commonest paediatric rheumatic dis- and leucopenia also can occur. Complete heart block can also order next to Juvenile Idiopathic Arthritis. Childhood SLE occur which needs early delivery and pacing in 50% of cases.
usually occurs in the age group of 5-16 years (Mean age - 12 years) with female predominance (5:1). It is said that female The risk of a second baby with CHB being born to a preponderance is lower in childhood but Indian experience mother with neonatal lupus is only about 10%. It is not worth- does not support this observation. The mean duration of ill- while to treat the pregnant mother with plasmapheresis and ness before diagnosis is about 1 year. Table 7 and 8 give the dexmathasone in an attempt to prevent the recurrence. When clinical and laboratory features noted in 2 different series on foetal monitoring does reveal presence of CHB and hydrops Indian children.26,27 Clinical features in children are generally in foetus, dexamethasone and plasmapheresis may succeed in similar to those described in adults but the disease tends to be more severe. Renal involvement is more common. Lymphad- The revised ACR classification criteria (1997) for enopathy is also seen more commonly in children.
Table 7 Clinical features of Indian children with SLE
Table 8 Laboratory features Indian children with SLE
References
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Prevalence of systemic lupus erythematosus in India. Lupus Children are extremely vulnerable to the psychologi- cal impact of both lupus as chronic illness and the medica- Hochberg MC. Prevalence of systemic lupus erythematosus in tions that dramatically change their appearance. The peer- England and Wales (1981-82). Ann Rheum Dis 1987; 46: group pressures may exert overwhelming effects on a child’s mind. The complex interaction of these unique challenges with Jonsson H, Nived O, Surfelt G. Outcome in systemic lupus the usual medical problems of SLE poses difficult dilemmas erythematosus: a prospective study of patients from a defined before the treating physician. Patient and family education as population. Medicine (Baltimore) 1989; 68: 141-50.
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20. Petri M, Bochemstedt I, Colman J et al. Serial assessment of Systemic lupus erythematosus in northern India: A review of glomerular filtration rate in lupus nephropathy. Kidney Int 1988; 329 cases. J Assoc Physicians India 1988; 36: 476-480 11. Madhavan R, Porkodi R, Ramakrishnan S et al. Systemic lupus 21. Gladman DD, Ginzler E, Goldsmith C et al. The development erythematosus- the Madras experience. J Assoc Physicians In- and initial validation of the Systemic Lupus International Col- laborating Clinics/ACR Damage index for SLE. Arthritis Rheum 12. Amin SN, Angadi SA, Mangat GK et al. Clinical profile of sys- temic lupus erythematosus in Western India. J Assoc Physi- 22. Gaitonde S, Pathan E, Sule A, Mittal G, Joshi VR. Efficacy of isoniazid prophylaxis in patients with SLE receiving long-term 13. Vaidya S, Samant RS, Nadkar MY, Borges NE. Systemic lupus steroid treatment. Ann Rheum Dis 2002; 61: 251-53.
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