Approach Considerations

The principal goal of therapy in lupus nephritis is to normalize renal function or, at least, to prevent the progressive loss of renal
function. Therapy differs depending on the pathologic lesion. [23, 37] It is important to treat extrarenal manifestations and other
variables that may affect the kidneys.
Corticosteroid therapy should be instituted if the patient has clinically significant renal disease. Use immunosuppressive agents,
particularly cyclophosphamide, azathioprine, or mycophenolate mofetil, if the patient has aggressive proliferative renal lesions,
as they improve the renal outcome. Immunosuppressives can also be used if the patient has an inadequate response or
excessive sensitivity to corticosteroids. [37, 38, 39]
Calcineurin inhibitors, especially tacrolimus, have demonstrated benefit in lupus nephritis. However, most studies have been
limited to Asian patients, and further research is required on long-term benefits and disadvantages. [40, 41, 42]
Treat hypertension aggressively. On the basis of beneficial effects in other nephropathies, angiotensin-converting enzyme
inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been routinely used to treat proteinuria in lupus nephritis.
Alter the diet according to the presence of hypertension, hyperlipidemia, and renal insufficiency. Restrict fat intake or use lipid-
lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome. Restrict protein intake if renal function is
significantly impaired.
Administer calcium supplementation to prevent osteoporosis if the patient is on long-term corticosteroid therapy, and consider
adding a bisphosphonate (depending on renal function).
Avoid drugs that affect renal function, including nonsteroidal anti-inflammatory drugs (NSAIDs), especially in patients with
elevated creatinine levels. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal
disease.

The first guidelines for managing lupus nephritis have been issued by the American College of Rheumatology. [45] Key points of
the guidelines are as follows:
 Patients with clinical evidence of active, previously untreated lupus nephritis should have a renal biopsy to classify the
disease according to International Society of Nephrology/Renal Pathology Society criteria
 All patients with lupus nephritis should receive background therapy with hydroxychloroquine, unless contraindicated; this
recommendation was based on a prospective controlled trial showing lower flare rates in those who continued
hydroxychloroquine, compared with those who switched to placebo [46]
 Glucocorticoids plus either cyclophosphamide intravenously (IV) or mycophenolate mofetil orally for induction in patients
with ISN class III/IV disease; patients with ISN/RPS class I and II nephritis do not require immunosuppressive therapy
 Administer ACEIs or ARBs if proteinuria is 0.5 g/24 h or more
 Maintain blood pressure at or below 130/80 mm Hg
Joint guidelines for the management of adult and pediatric lupus nephritis have also been issued by European League Against
Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA). The EULAR/ERA-
EDTA recommendations include the following [47] :
 Any sign of renal involvement can be an indication for biopsy, which should be performed within the first month after
disease onset, preferably before the institution of immunosuppressive treatment
 Use mycophenolate mofetil or or low-dose IV cyclophosphamide plus glucocorticoids as the initial treatment for patients
with ISN class III–IV Adisease
 In patients with adverse clinical or histological features, cyclophosphamide can be prescribed at higher doses, while
azathioprine is an alternative for milder cases
 For pure class V lupus nephritis LN with nephrotic-range proteinuria, use mycophenolate mofetil in combination with oral
glucocorticoids for initial immunosuppressive therapy
 Patients who improve after initial treatment should receive mycophenolate mofetil or azathioprine for at least 3 years;
patients who start on mycophenolate mofetil should continue on that agent
 Patients in whom mycophenolate mofetil or cyclophosphamide therapy fails should be switched to the other agent or to
rituximab

Pharmacotherapy for Lupus Nephritis Based on Stage

Classes I and II
Minimal mesangial (class I) lupus nephritis requires no specific therapy. [23]
Mesangial proliferative (class II) lupus nephritis may require treatment if proteinuria is greater than 1000 mg/day. Consider
prednisone in low-to-moderate doses (ie, 20-40 mg/day) for 1-3 months, with subsequent taper.
Classes III and IV
Patients with either focal (class III) or diffuse (class IV) lupus nephritis are at high risk of progressing to ESRD and thus require
aggressive therapy.
Administer prednisone 1 mg/kg/day for at least 4 weeks, depending on clinical response. Then, taper it gradually to a daily
maintenance dose of 5-10 mg/day for approximately 2 years. In acutely ill patients, intravenous (IV) methylprednisolone at a
dosage of up to 1000 mg/day for 3 days may be used to initiate corticosteroid therapy.
In patients who do not respond to corticosteroids alone, who have unacceptable toxicity to corticosteroids, who have worsening
renal function, who have severe proliferative lesions, or who have evidence of sclerosis on renal biopsy specimens, use
immunosuppressive drugs in addition to corticosteroids.
Both cyclophosphamide and azathioprine are effective in proliferative lupus nephritis, although cyclophosphamide is apparently
more effective in preventing progression to ESRD. Mycophenolate mofetil has been shown to be at least as effective as IV
cyclophosphamide, with less toxicity, in patients with focal or diffuse lupus nephritis who have stable renal function. [48, 49] It may
be used alone [48, 49] or sequentially after a 6-month course of IV cyclophosphamide. [50]
Appel et al studied 370 patients with lupus nephritis in a randomized open-label study and found no significant difference in
clinical improvement was observed with mycophenolate mofetil compared with IV cyclophosphamide. [51] The study included
induction and maintenance therapy, and both study groups received prednisone.
 Administer IV cyclophosphamide monthly for 6 months and every 2-3 months thereafter, depending on clinical response. The
usual duration of therapy is 2-2.5 years. Reduce the dose if the creatinine clearance is less than 30 mL/min. Adjust the dose
depending on the hematologic response. [52, 53] The gonadotropin-releasing hormone analogue leuprolide acetate has been
shown to protect against ovarian failure. [54]

Azathioprine can also be used as a second-line agent, with dose adjustments depending on hematologic response.
Mycophenolate mofetil was found to be superior to azathioprine in maintaining control and preventing relapses of lupus
nephritis in patients who have responded to induction therapy. [55]
In a 10-year follow-up of the MAINTAIN Nephritis Trial, which compared azathioprine and mycophenolate mofetil as
maintenance therapy of proliferative lupus nephritis, Tamirou and colleagues found that the two treatments resulted in similar
outcomes. Two deaths and one case of end-stage renal disease developed in the azathioprine group, versus three deaths and
three cases of end-stage renal disease in the mycophenolate mofetil group. [56]
Class V
Patients with membranous lupus nephritis are generally treated with prednisone for 1-3 months, followed by tapering for 1-2
years if a response occurs. If no response occurs, the drug is discontinued. Immunosuppressive drugs are generally not used
unless renal function worsens or a proliferative component is present on renal biopsy samples. Some clinical evidence indicates
that azathioprine, cyclophosphamide, cyclosporine, and chlorambucil are effective in reducing proteinuria. Mycophenolate
mofetil may also be effective.
In a study of membranous lupus nephritis, 38 patients were treated with corticosteroids and azathioprine; after 12 months of
treatment, 67% of patients had a complete remission and 22% had a partial remission, with only 11% resistant to
treatment. [57] Long-term follow-up of 12 years showed 19 episodes of renal flares. Retreatment with corticosteroids and
azathioprine showed similar responses.

CLINICAL CRITERIA--LUPUS
ACUTE CUTANEOUS LUPUS OR SUBACUTE CUTANEOUS
LUPUS
 Acute cutaneous lupus: lupus malar rash (do not count if
malar discoid), bullous lupus, toxic epidermal necrolysis
variant of SLE, maculopapular lupus rash, photosensitive
lupus rash (in the absence of dermatomyositis).
 Subacute cutaneous lupus: nonindurated psoriasiform
and/or annular polycyclic lesions that resolve without
scarring, although occasionally with postinflammatory
dyspigmentation or telangiectasias).
NON-SCARRING ALOPECIA
 Diffuse thinning or hair fragility with visibly broken hairs, in
the absence of other causes such as alopecia areata, drugs,
iron deficiency, and androgenic alopecia
SYNOVITIS INVOLVING 2 OR MORE JOINTS
 Characterized by swelling or effusion
 OR tenderness in 2 or more joints and at least 30 minutes
of morning stiffness
 SEROSITIS
Typical pleurisy for more than 1 day OR pleural effusions
OR pleural rub
Typical pericardial pain (pain with recumbency improved by
sitting forward) for more than 1 day OR pericardial effusion
OR pericardial rub OR pericarditis by electrocardiography
 In the absence of other causes, such as infection, uremia,
and Dressler’s pericarditis

CHRONIC CUTANEOUS LUPUS  RENAL

 Classic discoid rash localized (above the neck) or
generalized (above and below the neck), hypertrophic
(verrucous) lupus, lupus panniculitis (Profundis), mucosal
lupus, lupus erythematosus tumidus, chilblains lupus,
discoid lupus/lichen planus overlap.
 Seizures, psychosis, mononeuritis multiplex(in the absence
ORAL ULCERS OR NASAL ULCERS
 Oral: palate, buccal, tongue
 Nasal ulcers
 In the absence of other causes, such as vasculitis, Behcet’s
disease, infection (herpesvirus), inflammatory bowel
disease, reactive arthritis, and acidic foods
Urine protein-to-creatinine ratio (or 24-hour urine protein)
representing 500 mg protein/24 hours OR red blood cell
casts
NEUROLOGIC
of other known causes such as primary vasculitis), myelitis,
peripheral or cranial neuropathy (in the absence of other
known causes such as primary vasculitis, infection, and
diabetes mellitus), acute confusional state (in the absence
of other causes, including toxic/metabolic, uremia, drugs)
 HEMOLYTIC ANEMIA
LEUKOPENIA (<4000/MM3) OR LYMPHOPENIA
(<1000/MM3)
 Leucopenia at least once: In the absence of other known
causes such as Felty’s syndrome, drugs, and portal
hypertension.
 Lymphopenia at least once: in the absence of other known
causes such as corticosteroids, drugs, and infection
THROMBOCYTOPENIA (<100,000/MM3)
At least once in the absence of other known causes such as
drugs, portal hypertension, and thrombotic
thrombocytopenic purpura
IMMUNOLOGIC CRITERIA
 ANA level above laboratory reference range
 Anti-dsDNA antibody level above laboratory reference
range (or 2-fold the reference range if tested by ELISA)
 Anti-Sm: the presence of antibody to Sm nuclear antigen
 Antiphospholipid antibody positivity, as determined
byPositive test for lupus anticoagulant
The false-positive test result for rapid plasma reagin
Medium- or high-titer anticardiolipin antibody level (IgA,
IgG, or IgM)
The positive test result for anti–2-glycoprotein I (IgA, IgG, or
IgM)
 Low complement (C3, C4, or CH50)
 Direct Coombs’ test (in the absence of hemolytic anemia

LUPUS MANAGEMENT - ill patients require education and general prophylactic measures to prevent disease flares:

• Sunscreens and protective clothing are effective in avoiding photosensitivity reactions .

• The use of estrogen containing oral contraceptives is controversial in SLE, but many centers avoid these medications because
they may increase the disease activity.
• Avoidance of vasoconstrictive drugs are helpful in treating Raynaud's phenomenon, also patients with SLE may benefit from
vasodilator therapy.
• Low dose aspirin for patients with positive antiphospholipid antibodies to prevents thrombotic events .
• Psychological support is essential because SLE may cause depression and anxiety.
• Routine immunizations for influenza and pneumococci are recommended .

1- Arthralgia, mild arthritis, fever and serositis respond to NSAIDs .

2- Skin manifestations respond to hydroxychloroquine 400mg/d + topical steroid (hydroxychloroquine is also indicated in
arthralgia resistant to
NSAIDs) .

3- Corticosteroid therapy is the main subject of treatment.

- Steroids are used for almost all manifestations of lupus in doses ranging from extremely small alternate day doses to huge
pulsed intravenous doses .
- Prolonged steroid therapy usually lead to DM , accelerated atherosclerosis, osteoporosis, glucoma, cataract, avascular necrosis
and increased risk of
infections.
To avoid such toxicities, different cytotoxic drugs can be used to provide steroid sparing effect (see below).

Role of steroids
To control the inflammatory reaction --> prevent end organ damage.

Method
Give full dose of steroid 60-80 mg predinsolone / day till activity of the disease disappears i.e :
* Resolution of symptoms and signs.
* - ve Anti-DNA
* Normal C3 and C4

Then gradual withdrawal followed by low dose steroid as maintenance :

10-15 mg / day to prevent relapse and prevent end organ damage.
** Pulse steroid therapy can be used in severe cases (see later).

4- Immunosuppressive drugs
Used in severe disease activity e.g severe lupus nephritis or cerebral disease.

• Azathioprine (Immuran): - 2mg/kg/d orally. It is used when steroid alone is not fully effective. It is also a steroid sparing drug.
i.e it allows
a reduction of steroid dose. The side effects are leucopenia, anaemia & infections.
• Cyclophosphamide (Endoxan):
1-3 mg/kg/d orally, also it can be given as pulse therapy 0.5-1 gm/m Iv.
It is important to monitor the side effects e.g Infections, bone marrow depression and infertility.
This drug is extremely toxic so, it is reserved for the most severe disease manifestations.

• Cyclosporine (Sandimmun) and mycophenolate (myfortic) can also be used with severe disease activity and to avoid the side
effects of other
immunosuppressive drugs.

** Prolonged use of azathioprine may increase the risk of haematological malignancy .

5- Plasmapharesis can be used in cases with severe exacerbations refractory to steroid.

6- Immunoglobulin therapy is effective for thrombocytopenia of SLE .

Q : Pulse steroid therapy ?

Dose : 500 - 1000 mg methyl prednisolone/ day I.V. 3 - 5 days.

To be followed by full dose steroid until improvement (laboratory and clinical).
Then low dose steroid as maintenance 10 - 15 mg / day

** Pulse I.V cyclophosphamide in combination with pulse steroid is more effective.

Pulse steroid therapy can be used in SLE with severe activity. e.g. Vasculitis, cresentic GN, severe cerebral or haematological
disease.

Other indications of pulse steroid therapy :

1- Cresentic glomerulonephritis (rapidly progressive G.N.)

2- Multiple sclerosis
3- Optic neuritis.

Precautions :
• Prophylaxis for peptic ulceration by proton pump inhibitors.
• Control blood pressure.
• Control blood sugar.
• Isolation to guard against infection.

Course and prognosis of SLE :

• The course is characterized by remission and exacerbation.
• Chronic course occasionally seen.
• 5 years survival rate is about 90 %.
• Severe renal or neurological disease have the worst prognosis.