Systemic lupus erythematosus (SLE)

Systemic connective tissue diseases: Systemic lupus erythematosus (SLE)

 

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause which can affect the skin, joints, kidneys, lungs, nervous system, serous membranes and/or other organs of the body. Distinct immunologic abnormalities, especially the production of a number of antinuclear antibodies, are another prominent feature of the disease. The clinical course of SLE is characterized by periods of remissions and chronic or acute relapses. Women, especially in their 20s and 30s, are affected more frequently than men. Treatment is based on preventive measures, reversal of inflammation, prevention of organ impairment, and alleviation of symptoms.

Etiology

Although the specific cause of SLE is unknown, multiple genetic predispositions and gene-environment interactions have been identified (see the chart in the image below). This complex situation perhaps explains the variable clinical manifestations in persons with SLE.

·                     SLE has a modest recurrence rate in families: 8% of affected patients have at least one first-degree family member (parents, siblings, and children) with SLE; this is in contrast to 0.08% of the general population. In addition, SLE occurs in both twins in 24% of identical twins and 2% of nonidentical twins, which may be due to a combination of genetic and environmental factors. Some studies have synthesized what is known about the mechanisms of SLE disease and genetic associations. At least 35 genes are known to increase the risk of SLE.  A genetic predisposition is supported by 40% concordance in monozygotic twins; if a mother has SLE, her daughter’s risk of developing the disease has been estimated to be 1:40, and her son’s risk, 1:250.

Patogenesis

The pathogenesis of lupus remains unclear although the concept of apoptosis goes some way to explaining how the immune system may recognise predominantly intracellular antigens. Autoantigens are released by necrotic as well as apoptotic cells. Defects in the clearance of apoptotic cells have been described in SLE which may lead to aberrant uptake by macrophages which then  present the previously intracellular antigens to T and B cells thus driving the autoimmune process. Recent work has expanded these concepts and dissected out possible defects in clearance of apoptotic bodies including complement deficiencies, defects in macrophage handling and  presentation of these antigens to the immune system. The most striking recent studies have demonstrated the development of autoantibodies years  before the onset of clinical features of SLE and the antiphospholipid syndrome (APS). Antinuclear antibodies occurre earlier than antiDNA antibodies and a significant number of these patients had a rise in the anti-DNA titres just prior to diagnosis. Interestingly, anti-Sm and anti-RNP antibodies appeared shortly before diagnosis suggesting a crescendo of autoimmunity resulting in clinical illness. Classification

The nature of the disease

ü    acute

ü    subacute

ü    chronic:

Ø     recurrent arthritis,

Ø     discoid lupus,

Ø     Raynaud’s syndrome,

Ø     thrombocytopenic purpura syndrome,

Ø     Sjogren syndrome

Stage of activity

ü    Active

Ø     high

Ø     moderate

Ø     minimal

ü Moderate

ü Severe

 

CLINICAL MANIFESTATIONS

Musculoskeletal involvement

Joints

Arthralgia occurs in about 90% of all patients with SLE. Characteristically, it is polyarticular, symmetrical, episodic and flitting iature. The patients’ symptoms often exceed the objective clinical findings and usually there is no clinically overt arthritis. Synovial effusions are uncommon and of small volume when they do occur. However, approximately 10% of SLE patients do have a deforming Jaccoud’s arthritis. In contrast to patients with rheumatoid arthritis, the deformities are not usually associated with synovial hypertrophy or bony erosions.

Muscles

Clinically obvious muscle involvement has been reported in 30-50% of SLE patients. However, myalgia, muscle weakness and tenderness, may be due to a variety of other complications. Thus both corticosteroid and rarely chloroquine therapy may cause a myopathy. In addition, myalgia may be induced by an adjacent arthralgia, although only 5% of lupus patients have met the ACR criteria for both SLE and polymyositis. 

Dermatological involvement

Cutaneous lesions may occur in up to 85% of SLE patients. The butterfly rash is erythematous, often blotchy, and found mainly over the malar bones and across the bridge of the  nose. Vasculitic  skin  lesions are usually found at the nailfolds and finger tips  or on the extensor surface of the  forearm. When they occur around the malleoli, they may lead to tender, deep, leg ulcers which can take months to heal.

Many SLE rashes are exacerbated by ultraviolet light and indeed generalized lupus flares may  follow exposure to direct sunlight with inadequate protection.  A particularly photosensitive rash  is subacute cutaneous lupus erythematosus (SCLE) which is often associated with anti-Ro antibodies.

Lupus nephritis

More than 70% of patients with SLE have renal involvement at some stage of their disease. These  descriptions allow better communication between pathologists translating static images from histology slides into meaningful descriptions of the huge variety of biopsy appearances for clinicians. Of the different pathological classes, diffuse proliferative glomerulonephritis (Class IV) has the worst

prognosis, resulting in 11-48% of patients with end stage renal disease at 5 years.

 

Lungs

The immunosuppressive therapy required by many SLE patients predisposes them to concurrent infection. The lungs are a frequent target for this “secondary” infection and bacteria (including tubercule bacilli), viruses and fungi may all cause pneumonia in lupus patients.Parenchymal alterations, attributable to SLE itself, have been described in 18% of patients. These patients had interstitial fibrosis, pulmonary vasculitis and interstitial pneumonitis.

Heart

Pericardium

Abnormalities of the electrocardiogram, notably of the T wave, are the most frequent

manifestation. A pericardial rub may be more common than a significant pericardial effusion. Histological abnormalities vary from occasional foci of fibrinoid degeneration and inflammatory cell infiltrates to far more extensive lesions. Adhesive chronic pericarditis and very large effusions causing tamponade are very rare.

Myocardium

Whilst true myocardial involvement is less frequent than pericardial disease, prolongation of the PR interval (approximately 10%), fibrinoid degeneration, myocardial infarction and coronary stenosis due to arteritis are occasionally seen. New imaging techniques such as cardiac MRI suggest that myocardial involvement may be more common than previously thought.There is increasing evidence that premature accelerated atherosclerosis considerably increases the risk of cardiovascular events in patients with SLE and this is described in a separate module of this course.

Valves

Systolic murmurs are frequently heard in around 30% of SLE patients. However, they probably reflect the hyperdynamic circulation consequent upon the anaemia often found in these individuals. In contrast, diastolic murmurs are uncommon. Libman-Sacks endocarditis has long been described as a feature of SLE. Although found in up

to 50% of autopsied cases, it rarely causes clinically significant lesions. Histologically, the lesions are small (1-4 mm) vegetations (verrucae) comprising proliferating and degenerating valve tissue with fibrin and platelet thrombi. They are most frequently found adjacent to the edges of the mitral and tricuspid valves. aPL may contribute to the development of Libman-Sacks endocarditis and studies suggest that there is a selective deposition of aPL and complement within the walls of the small junctional vessels in the active portions of the verrucous endocardial lesions.

Central nervous system lupus

The ACR classification criteria for central nervous system (CNS) lupus has changed

considerably from seizures and psychosis. The ACR nomenclature now includes 19 different syndromes that are classifiable . An emerging concept is the distinction between CNS manifestations due to lupus and those due to the APS. A wide variety of neuropsychiatric manifestations attributable to APS have been described including strokes, seizures, movement disorders, transverse myelopathy, demyelination syndromes, transient ischaemic attacks, cognitive dysfunction, visual loss and headaches including migraine.

Ocular Manifestation 

Retinal vasculitis is a serious manifestation; blindness can develop over a few days, and aggressive immunosuppression should be instituted. Examination shows areas of sheathed, narrow retinal arterioles and cytoid bodies (white exudates) adjacent to vessels. Other ocular abnormalities include conjunctivitis, episcleritis, optic neuritis, and the sicca syndrome.

Esophagus

Lupus patients occasionally complain of dysphagia or odynophagia. This can be multifactorial from hypomotility, from reflux disease, or from candidiasis from immunosuppression. If the symptoms are severe, they deserve a regular dysphagia evaluation with motility studies, x-rays, and maybe an endoscopy. Although treatment is directed at the cause, motility drugs are no longer favored due to their arrythmogenic potential. Antireflux medications or antifungals are used when appropriate.

Abdomen

Abdominal pain is a diagnostic challenge in SLE and is probably one of the most clinically threatening GI manifestation to be aware of. Min and colleagues looked at causes of acute abdominal pain in SLE patients in emergency departments (EDs). They documented that 59.1% of visits to the ED by SLE patients were from pain due to ischemic bowel disease. The other causes were splenic infarcts, renal venous thrombosis, pancreatitis, serositis, upper GI bleeds, pelvic inflammatory disease, and ectopic pregnancy. Peptic ulcer disease with perforation also manifested as an acute abdomen in a small number of patients with SLE and concomitant NSAID use.  Treatment of acute abdominal pain is directed at the cause, with appropriate medical or surgical management of the presenting manifestation.

Intestines

In the bowel, SLE can manifest with vasculitis, malabsorption, or dysmotility. Mesenteric vasculitis in lupus can manifest as an acute abdomen with fever, nausea, vomiting, diarrhea, and rectal bleeding or with the characteristic mesenteric ischemic pain related to meals.

Pancreas

Pancreatitis in lupus is uncommon and could occur in a setting of high SLEDAI scores, antiphospholipid antibody syndrome, and probable steroid use. The more likely causes, as in any other setting, are gallstones, alcohol, and hypertriglyceridemia. Treatment is the same as for pancreatitis from any other cause and includes nothing by mouth, IV fluids, withholding causal drugs, and, rarely, use of steroids if the cause is established by exclusion.

Liver

Drugs, viruses, fatty infiltration, or congestion have been implicated as more common causes of liver enzyme abnormalities in SLE patients. Hepatitis from lupus (lupus hepatitis), although uncommon, manifests as a mild elevation in liver enzymes (aspartate transaminase [AST], alanine transaminase [ALT)], lactate dehydrogenase [LDH], alkaline phosphatase), usually in a setting of active lupus. Such biochemical liver abnormalities from an SLE flare have a tendency to reverse with steroids. Lupoid hepatitis is a separate entity and is considered a subset of chronic active autoimmune hepatitis, where the liver is the main organ of involvement. Patients with lupus hepatitis and lupoid hepatitis can have arthralgias, hypergammaglobulinemia, and positive ANAs. Serologic differentiation may be possible at times and in general involves the presence of anti–ribosomal P and dsDNA autoantibodies in lupus hepatitis versus anti–smooth muscle and auto–liver-kidney-mitochondrial (LKM) antibodies in lupoid hepatitis. Definite differentiation is only possible on histology, which shows a lobular involvement in lupus hepatitis versus rosetting of liver cells and dense lymphoid infiltrate in lupoid hepatitis.

Haematological abnormalities

Red blood cells

A normochromic, normocytic anaemia is frequently found in SLE patients, with concomitant low levels of both the serum iron and iron binding capacity. This abnormality appears to be related, as in other diseases, to chronic inflammation and shunting of elemental iron from erythroblasts to macrophages.Iron-deficiency anaemia may be induced by non-steroidal anti-inflammatory drugs, which can cause gastrointestinal haemorrhage. Excessive blood loss from menorrhagia, sometimes related to severe thrombocytopenia, may have the same effect. Haemolytic anaemia as detected by the Coombs’ test is another rare feature of SLE. Autoimmune thrombocytopenia occasionally manifests simultaneously with haemolytic anaemia: this

condition is known as Evan’s syndrome.

Platelets

Two forms of thrombocytopenia (platelet count < 100 x 109/l) are found in SLE. Firstly, it may be encountered in a chronic form, generally associated with mild disease. Secondly, it may occur in an acute form, similar to idiopathic autoimmune thrombocytopenic purpura. This latter association is with disease carrying a greater morbidity and mortality. Platelet destruction appears to be mediated by anti-platelet antibodies and aPL are also associated with thrombocytopenia as well as with thrombosis.

White blood cells

Persistent leucopenia (< 4.0 x 109/l) is one of the ACR criteria for the classification of SLE. It probably results from a combination of destruction of white cells by autoantibodies, decreased marrow production, increased or marginal splenic pooling, and complement activation. It should also be noted that the immunosuppressive drugs used in the treatment of SLE may cause a marked leucopenia.

Serological abnormalities

The serum from SLE patients may bind to an extensive array of molecules including nucleic acids (antinuclear antibodies) and phospholipid binding proteins (lupus anticoagulant, anticardiolipin antibodies, β2 glycoprotein 1 antibodies). Antibodies may also be detected against diverse cells including leukocytes, erythrocytes, platelets and neurones. In addition to these autoantibodies, numerous other abnormalities are evident, including the LE cell phenomenon, hypocomplementaemia, elevated levels of acute phase proteins, gamma globulins and circulating immune complexes.

Non-specific features

Fever, lymphadenopathy, hair loss and Raynaud’s phenomenon are all commonly found in SLE patients. Fever in lupus patients may be striking and often requires extensive investigation to exclude concurrent infection, although a normal CRP in this context usually suggests a low likelihood of sepsis.

Lymphadenopathy may also be dramatic in SLE, to such an extent that lymph node biopsy may have to be performed to exclude malignancy. Some patients seem more prone to this feature than others and in this group the degree of lymphadenopathy may reflect general disease activity.

Splenomegaly occurs in about 10% of patients.

The clinical diagnosis of SLE hinges on careful and very thorough assessment of the

presenting clinical features, examination of all the organ systems and selected investigations.

Clinical symptoms

Symptoms often occur intermittently and cumulatively over many months and years. Oral ulcers, arthralgia, hair fall, Raynaud’s phenomenon, photosensitive rashes, pleuritic chest pains, headaches, fatigue, fevers and lymphadenopathy are just a few of the many non-specific presenting features of this disease.

There are no diagnostic criteria for lupus and the ACR classification criteria are often misused in this context and can result in missed diagnosis/under-treatment. For example a patient may present with arthritis, Raynaud’s phenomenon, malaise, fevers, lymphadenopathy, oral ulcers and a positive ANA. This patient clearly may have SLE but does not fulfil the 4 criteria needed for classification by the ACR criteria but investigation and treatment should not be delayed until these criteria are fulfilled. The ACR criteria were specifically designed to be highly specific for research studies to enable consistency between studies and have been updated to include antiphospholipid

antibodies in the criteria.

The objective assessment of lupus has depended on a number of disease activity scoring

systems which usually give a single numeric value.

Diagnostic criteria

 

Laboratory and instrumental investigations

Clinical examination of all organ systems including routine urinalysis and blood pressure measurement is mandatory. Simple investigations may yield useful information. For example, a grossly elevated erythrocyte sedimentation rate (ESR) with a normal C-reactive protein (CRP) is a strong pointer to lupus and related connective tissue diseases. Blood count abnormalities such as anaemia, neutropenia, lymphopenia and thrombocytopenia are also common. Antinuclear antibodies are highly sensitive but not specific and anti-dsDNA antibodies are specific but not sensitive and it is important to recognise that a negative result for anti-dsDNA antibodies does not exclude a diagnosis of lupus.

This table is not a standardized guideline, and tests can vary in different clinical settings. The clinical assessment and tests must be combined to make an appropriate diagnosis of SLE.

 

TREATMENT

General approach to the drug therapy of SLE

Since there is a range of severity of disease manifestations, proper categorization based on clinical and laboratory features is the first therapeutic step. The following scheme is recommended:

Category I (Mild SLE)

 Characterised by arthritis, arthralgia, myalgia, fatigue, mild mucocutaneous involvement, low-grade fever, mild serositis, lupus headache,  musculoskeletal complaints are the commonest features of SLE. For mild symptoms, NSAIDs and analgesics may suffice. NSAIDs can occasionally cause adverse effects which may resemble those produced by the disease itself such as proteinuria, edema, renal failure and aseptic meningitis. In some patients, the above symptoms may not be alleviated with NSAIDs alone, and they should be prescribed antimalarials (chloroquine, hydroxychloroquine). These drugs are particularly useful for cutaneous manifestations of SLE. These agents have multiple properties: immunosuppressive anti-inflammatory and sun-blocking. They are also reported to possess anti-platelet and cholesterol lowering effects. The drug of choice is hydroxychloroquine (200 mg BD for 3 months and then 200 mg daily). The maintenance dose must not exceed 6 mg/kg/day. Although the incidence of retinal toxicity is very low, annual monitoring of vision with perimetery using a red object is recommended (for chloroquine, 6-monthly monitoring is desirable). The drug must be discontinued if a central scotoma is detected at any stage. Other significant side effects include nausea, pruritus, hyperpigmentation, myopathy and rarely psychosis. Use of hydroxychloroquine during pregnancy is controversial. When antimalarials are withdrawn after prolonged administration, some patients may develop a relapse of lupus activity. In refractory cases, quinacrine may be combined with hydroxychloroquine. Alternatives include dapsone and thalidomide. Quinacrine and thalidomide are, however, not available in India. Patients not responding to the above measures may be treated with low-dose steroid therapy (Prednisolone 0.3- 0.5 mg/kg/day) for 4-6 weeks followed by slow tapering. For lupus dermatitis, there is also a role of local steroids, including topical creams and ointments and injections into unresponsive skin lesions. However, the steroid cream application for facial rash is not recommended. Adequate protection against sun is essential (vide supra).

Category II (Moderate SLE)

Characterised by high-grade fever, toxaemia, severe mucocutaneous manifestations, marked photosensitivity, moderate to severe serositis, lupus pneumonitis, mild to moderate myocarditis, mesangioproliferative or minimal change lupus nephritis, haemolytic anaemia and thrombocytopenia For moderate and severe manifestations, prednisolone 1 mg/kg orally per day is the drug of choice. Antimalarials may be administered concomitantly. High dose of steroid must be continued till disease activity is well controlled that usually takes up to 6 weeks when it should be tapered off slowly over 6 to12 months. In a toxic appearing patient, the administration of intravenous pulse methylprednisolone (15 mg/kg, max. 1 g) over an hour for 3 or 5 consecutive days may achieve rapid control of lupus activity. Dexamethasone 100 mg is a good, cheap and equally effective alternative steroid for pulse therapy. Although rare, arrhythmias, accelerated hypertension, psychosis, seizures and sudden death have been reported with pulse therapy. The pulses should be followed by oral prednisolone. Calcium supplements (1 gm/day) and vitamin D (800 units/day) prescribed along with steroids retard osteoporosis. Alendronate 10 mg daily or 70 mg once a week is a good antiresorptive drug for prevention of osteoporosis in patients starting on long-term steroid therapy. A maintenance dose of oral steroid (beyond 6 months) is not necessary in the majority of these patients and most often it is possible to maintain the remission with antimalarials and intermittent use of NSAIDs. INH prophylaxis in Indian patients has been a point of debate because of fear of promoting INH resistance.

Category III (Severe SLE)

Characterised by organ/life-threatening features such as focal/diffuse proliferative glomerulonephritis with or without azotaemia/hypertension, lupus cerebritis with recurrent seizures, acute confusional state, coma; systemic necrotizing vasculitis such as one causing peripheral gangrene, GI bleeding or mononeuritis multiplex. A combination therapy consisting of high-dose daily oral prednisolone (40-60 mg/day) and intravenous cyclophosphamide pulses (0.75 gm/m2, maximum of 1 g, over 1 hour) is recommended. The cyclophosphamide pulses are given once a month for 6 months by which time usually remission is achieved and then a maintenance pulse is administered every 3 months for a total of 2 years of cytotoxic therapy. Prednisolone is tapered off or reduced to a very low dose i.e. 5-7.5 mg per day by 6 months. At least two-thirds of patients maintain a long-term remission after this treatment regimen. Haemorrhagic cystitis is rare if attention is paid to adequate hydration after the pulse and prompt voiding of bladder and co-administration of MESNA. The overall risk of irreversible ovarian failure was noted to be 39% in one study. It was much higher for women aged more than 30. Infertility is common in men as well and sperm banking is recommended, if facilities are available. Bone marrow suppression and secondary infections (Herpes zoster, tuberculosis, pneumocystis carinii, staphylococcus, pseudomonas etc.), sclerosing cystitis and bladder carcinoma, are the other adverse outcomes. Some authorities recommend the above regimen for induction of remission (the first 6 months), which is then maintained with azathioprine 2-2.5 mg/kg/day for about 2 years. Alternatives include intravenous pulses of steroids on 3 consecutive days each month, daily oral administration of cyclophosphamide (2 mg/kg/day) or azathioprine from the beginning or a combination of these two agents along with oral prednisolone. The latter is believed to be the most potent (and the most toxic) regimen. Cyclophosphamide based regimens have been shown to be superior in achieving renal preservation. Plasmapheresis, methotrexate, cyclosporine and mycophenolate mofetil are other options. Progressive organ damage may still occur over several years despite achieving good short-term remissions in these patients.

Category IV (SLE with miscellaneous features)

Characterised by antiphospholipid syndrome (recurrent DVT, CVAs, recurrent foetal loss etc.), pure membranous lupus nephritis, chronic sclerosing lupus nephritis, seizures without other evidence of lupus activity, behavioural disorders without other serious manifestations, resistant thrombocytopenia or haemolytic anaemia Immunosuppressive therapy does not play any significant role in these conditions. Treatment of antiphospholipid syndrome is described in appendix.

Other specific entities:

 Transverse myelitis : Requires aggressive treatment with prednisolone orally 1.5 mg/kg/day and IV cyclophsophamide bolus. If there is no improvement, plasmapheresis should be considered.

Seizures: For generalized seizure, phenytoin and barbiturates are used and for focal, carbamazepine, valproate or gabapentin is used.

Headaches: Most patients respond to NSAIDs. In intractable cases steroid may be used. Chorea: No specific therapy is required.

Cranial /autonomic and peripheral neuropathy: Oral prednisolone in a dose of 1mg/kg/day is useful.

Cognitive dysfunction: Consider reducing the dose of prednisolone. If associated with APS, anticoagulate.

Principles of treatment of lupus nephritis

General measures: It is advisable to restrict salt if hypertension is present, fat if hyperlipidemia or nephrotic syndrome is present, protein should be restricted if azotaemia is present and calcium should be supplemented with steroid therapy. Meticulous control of hypertension is desirable. Pregnancy should be avoided during active lupus nephritis with suitable contraception (vide infra). NSAIDs should be avoided in the presence of impaired renal function. Immunosuppressive therapy: This is generally guided by the WHO Class of lupus nephritis.

1. Class I: Immunosuppressive therapy is not indicated.

2. Class IIa: Immunosuppressive therapy is not indicated.

3. Class IIb: If proteinura is > 1 gram/24 hours, antidsDNA is high and C3 is low, prednisolone should be administered at a dose of 20 mg daily for 6-12 weeks, followed by tapering over next 3 months.

4.Class III & IV: Protocol for this group is already described above (See Category III under management).

5. Class V: Described under management above (Category IV). A high chronicity index correlates with poor renal outcome with progression to end stage renal disease despite treatment. High activity Index is also associated with poor outcome if not treated aggressively with appropriate immunosuppressive therapy. Patients with high chronicity index and serum creatinine more than 3 mg/dL should not be treated aggressively unless activity index is also high. If serum creatinine is chronically high and more than 5 mg/dL, aggressive immunosuppressive therapy is harmful. Such patients will be better managed with dialysis and transplantation in due course.

Treatment of APS This can be considered under the following heads:

1. Deep venous thrombosis: The main purpose of treatment here is to prevent pulmonary embolism. Standard measures include bed-rest, elevation of the affected limb to allow the oedema and tenderness to subside and anticoagulant therapy. Heparin and warfarin should be started simultaneously so as to allow an overlap of about 5 days. INR should be adjusted between 3 and 4 on long-term warfarin therapy. The duration of warfarin therapy is life-long in patients with recurrent venous thrombosis.

2. Acute arterial thrombosis: In a patient with APS this usually means a TIA or stroke, with MI and digital gangrene being less common. In some patients with acute stroke (< 3 hours duration), thrombolytics can be used but the standard of care is usually heparin followed by warfarin. Low-dose aspirin is strongly recommended in patients who continue having thrombotic events despite full anticoagulation. APS patients with acute MI can be treated with thrombolytics, angioplasty or coronary stents. Peripheral arterial thrombosis can be treated with thrombolytics or heparin or angioplasty.

3. Catastrophic APS: These patients develop thrombosis in multiple organs and the features mimic DIC and TTP. Oral contraceptives and other drugs, pregnancy, infection and surgical procedures have been identified as predisposing factors.