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The Breakthrough in the Treatment of Lupus Nephritis by the John Darmawan Protocol (JDP).

Remission under intravenous and oral therapy is achieved after 2-4 months initiation of the JDP

Remission sustained by oral drugs is achieved after 5.5-7.5 months since initiation of the JDP

Remission without drug is obtained after 3.5-4.5 years since initiation of the JDP

Systemic Lupus Erythematosus (SLE) or usually called Lupus is an autoimmune disease of unknown cause(s) and diverse manifestations. History of 5-years survival rate before the advent of Prednisone or its derivates is available: 5-years survival rate is around 15% in the third world and 50% in the first and second world.

When Lupus is not adequately controlled with medications, Nephritis will appear after
2-4 years and is called Lupus Nephritis. When inadequately treated Lupus Nephritis is potentially fatal.

With availability of Cyclophosphamide and Azathioprine (Immunosuppressants) combined with Prednisone, the 5-years survival rate improved to about 60% in countries of the South and 80-90% in countries of the North.

The goal of therapy is to achieve Remission. Remission can be measured with 1 of the 6 validated outcome measures. The JDP Protocol applies the Systemic Lupus Activity Measures (SLAM) Score. When the SLAM Score is less than 1 and Erythrocyte Sedimentation Rate (ESR) is less than 20 mm per hour, the patient is in Remission. The SLAM Score measures the disease manifestations in almost all organs of the Lupus patient.

The JDP is a Step-down Bridge Protocol of Intravenous and Oral Combination of 6 Immunosuppressants. It is applied in a patient with Renal Biopsy WHO Class III, IV, and V. Lupus Nephritis with WHO Class I, II, and VI is not prescribed the JDP. Class I and II do not require the JDP for therapy. Class VI is irreversible whatever treatment is given. Class VI evolves into total renal failure with dialysis and subsequent death by infection.

The principle of the JDP is to induce Remission in the shortest possible period of time, before Class VI renal biopsy occurs or Chronicity Index has deteriorated to more than 5. By intensive daily administration of intravenous combination of 4 Immunosuppressants Remission is achieved. The 4 intravenous Immunosuppressants comprise Cyclophosphamide, 5-Flurouracil, Methylprednisolone, and Methotrexate.

Remission under intravenous and oral therapy is acquired after 2-4 months since initiation of treatment. The 24-hours urine Albumin (albumin in the urine) becomes negative or Micro-Albumin achieves normal value over a period of 2-4 months.
The Remission achieved is sustained by oral combination of 2 Immunosuppressants, while the intravenous therapy is tapered off after 5.5-7.5 months since initiation of treatment. This is called Remission with oral Drugs. The oral therapy is initiated together with the intravenous therapy for initial loading. The oral therapy will attain a serum level effective in maintaining ESR of less 20 mm per hour when the intravenous therapy is tapered off.

The oral therapy consists of Mycophenolate Mofetil and Methotrexate/Cyclosporine and must be continued for at least 2 years. After 2 years in Remission, the oral drugs are tapered off over a period of 1 year. If no flare occurs after oral drugs are tapered off then Remission without Drug is achieved in Lupus Nephritis after 3.5-4.5 years since initiation of the JDP.

Flare is defined when the SLAM Score rises to more than 1 and the ESR becomes abnormal (more than 25 mm per hour). Early (within 1 week) Flare of Lupus Nephritis must be immediately suppressed by reinstitution of the JDP to maintain short, medium, and long-term Remission.

To induce Remission under intravenous and oral therapy, the JDP must be administered daily 5 X weekly until ESR drops to less than 40 mm per hour. This is to avoid weekly cumulative dose induced adverse effects.

After ESR dropped to less than 40, 30, and 25 mm/hour (men < 30, < 20, and < 15 mm), the IV sessions are tapered to 3X, 2X, and 1X weekly respectively. When ESR is < 20 (women) or < 10 mm (men) disease is controlled. When disease is controlled, the IV session is tapered to once fortnightly (in conjunction with switching IV to once weekly oral equivalent dosage of Methotrexate), 4-weekly, 8-weekly and then terminated to Remission with oral Drugs.

The variable schedules in achieving various types of Remisions

1. Induction of Remission over 1-2 months after initiation by the JDP
2. Reduction of weekly IV sessions over 1-2 months
3. Remission achieved after 2-4 months
4. Tapering off intravenous sessions after 3.5 - 5.5 months since initiation of the JDP
5. Remission with oral Drugs after 5.5-7.5 months since initiation of the JDp
6. Consolidation of Remission with oral Drugs over 2 years
7. One year taperinf off oral drugs
8. Remission without Drug achieved after 3.5 - 4.5 years including Radiological
   Remission since initiation of the JDP.

Remission without drug is not a cure for Lupus Nephritis. Flare can be induced by mental and physical stress, sunlight, a viral infection, and after delivery of a baby.

The adverse effects of the 6 Immunosuppressants are listed in a leaflet in the drug package. Neupogen, Recormon, and combination of Epineprine+Methylprednisolone can overcome blood toxicities in a relative short period of time. Gastrointestinal toxicities such as anorexia, nausea, vomiting, diarrhea, including allergy can be treated and prevented.

The dreaded blood toxicities of low white blood cell, red cell, and thrombocytes count are avoided by daily intravenous low dosages of the immunosuppressants and low total frequency of administration, limited weekly and total cumulative dosages, and limited period of exposure.

The Lupus Nephritis Chronicity Index from The National Institute of Health, Bethesda, Maryland, USA, requires complex and sophisticated calculation. When the Chronicity Index is more than 5, which indicates Lupus Nephritis cannot achieve Remission.
The Lupus Prognosis Index is a simple tool used by the JDP to indicate when prognosis is dubious. The JDP will fail when Lupus Prognosis Index is 6 or more (Chronicity Index is 6 or more).

The Lupus Prognosis Index
Lupus or SLE by itself has a Prognosis Index of 2 plus 1 or more of the following.

Each of the following has a Prognosis Index of 1
1. Lupus Dermatitis
2. Lupus Pleurisies with effusion
3. Lupus Pericarditis with effusion
4. Lupus Nephritis (renal biopsy WHO Class < 6)

Each of the following has a Prognosis Index of 2.
1. Nephrotic Syndrome
2. Lupus Profundus
3. Lupus Pulmonum
4. Lupus Vasculitis (Cerebral Lupus with stroke)
5. Lupus Avascular Osteonecrosis of the joint(s)
6. Neuropsychiatric Lupus
7. Lupus Myocarditis.

When a patient shows up with SLE and Lupus Nephritis, the Prognosis Index is 4. With additional Pericardial Effusion the Lupus Prognosis Index is 5 and is still treatable by the JDP. However, when the Lupus Prognosis Index is 6 or more than the JDP is inclined to fail such as SLE+Lupus Pulmonum+Lupus Vasculitis.

Total Immunosuppressant-naivety is defined when the patient has never been treated with Cyclophosphamide, 5-Flurorouracil, Methylprednisolone, Methotrexate, and Mycophenolate Mofetil, and Cyclosporine. Partial Immunosuppressant-naivety is defined when the patient has been treated with several of the 6 Immunosuppressants. Total Immunosuppressant non-naivety is defined when the patient has been treated with all the 6 Immunosuppressants for example when a flare occurs. These naivety and non-naivety have implication for the outcome of therapy by the JDP.

Cyclophosphamide, 5-Fluorouracil, and Methylprednisolone are not given by oral route because of:

Intravenous	versus	Oral administration
Faster efficacy Maximum efficacy Effect lasts longer Minimum adverse effects		Slower efficacy Minimum efficacy Effect last shorter Maximum adverse effects

Nowadays 5, 10, 15, 20, and 25- years survival rate are important for the patients with Lupus Nephritis. Oral corticosteroid besides its standard adverse effects, prove to be cumulative damaging to the kidneys after 15 years. This may have implication in
20-years survival rate.

Hematological adverse effects are very rarely encountered, but mild gastrointestinal ones oocur in 25% of the patients treated with the JDP. These can be easily overcome Or prevented.
 

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