› News Archive

› Events Archive

New facts on the treatment of Lupus Nephritis

Introduction
Biopsy of the kidneys is required to confirm diagnosis of Lupus Nephritis. Besides the diagnosis, biopsy is needed to determine the appropriate treatment. Depending on WHO Classification of biopsy, treatment has been dependent on Prednisone.

Oral prednisone or prednisolone or Methylprednisolone has been the standard first-line drugs for treatment of Lupus Nephritis. Depending on the type of WHO Class biopsy Prednisone has been given for 4-12 weeks and then tapered off.

In WHO Class IV biopsy Cyclophosphamide is added when there is no response after 12 weeks with Prednisone. Cyclophosphamide has to be taken for at least 2 years if tolerated. If there is still no response Azathioprine is additionally tried. Unfortunately, in the meantime Nephrotic Syndrome in the minority of these patients has developed.

Nephrotic Syndrome
Nephrotic Syndrome if not controlled adequately, develops into End Stage Renal Disease
or WHO Class VI biopsy. So far nothing helps in WHO Class VI biopsy. Dialysis or kidney transplantation must be considered when End Stage Renal Disease is reached.

The high dosages of Prednisone, Cyclophosphamide, and Azathioprine induced adverse effects. When these adverse effects are not tolerated, dropouts of the patients ensue.
Notwithstanding the combination of Prednisone with Cyclophosphamide plus Azathioprine death still occurs in 30-40% of patients in WHO Class IV Lupus Nephritis (Data from National Institute of Health).

A new fact is discovered recently with the long-term use of Prednisone.
Oral corticosteroid is cumulatively damaging to the kidneys. After > 15 years the renal damage is mainly caused by the oral corticosteroid taken daily*.

*Gladman DD, Urowitz MB, Rahman P, Ibanez D, Tam LS. Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol. 2003 Sep;30(9):1955-9.

This new fact creates a dilemma for the physician and patients with Lupus Nephritis.
When the SLE is prescribed at the age of 15-25 years, sometimes it could not be tapered off without flare. Flare is defined when the disease returns. Consequently, long-term ingestion of Prednisone is the way out. Corticosteroid-induced Renal Disease occurs besides Lupus Nephritis when the patients reached the age of 35-45 years.

The National Institute of Health (USA) Recommendations
The National Institute of Health, USA, solves the dilemma by recommendation of a new drug’s combination. Intravenous Cyclophosphamide+Methylprednisolone and oral Mycophenolate Mofetil+Cyclosporine are indicted in WHO Class IV biopsy. These combinations of immunosuppressants when administered at the minimum effective dosages are safe and effective.

The WHO-ILAR COPCORD Stage II Treatment of the Autoimmune Diseases has developed an ingenious method of intravenous administration. Intravenous Methylprednisolone + Cyclophosphamide is administered for a relatively short period of 5.5 to 7.5 months. This includes the period of almost 4 months in tapering off intravenous therapy.

With an effective low ranging dosages of 25-100 mg Cyclophosphamide and 25-125 mg Methylprednisolone no hematogenic adverse effects have been encountered. With additional weekly intravenous weekly 5-12.5 mg Methotrexate efficacy is increased without additional adverse effects. Dose-dependent adverse effects are minimized by using the minimum effective dosages of the immunosuppressants in combination.

Gastrointestinal adverse effects are common. However, these can be prevented: nausea and vomiting by granisetron, diarrheas by spasmolytics, and gastroduodenal signs and complaints by proton pump inhibitors. There are patients whose gastrointestinal system has been abused over several decades that they cannot take anymore-oral medications.

Methods of the Step-down Bridge Protocol of Intravenous and Oral Combination of 5 Immunosuppressants
The principles of the WHO-ILAR COPCORD Stage II novel method of administration is:

1. induction of Remission by 5X weekly intravenous 25-125 mg Methylprednisolone +25-100 mg Cyclophosphamide;

2. maintenance of Remission with bid/tid of the oral combination of 250-500 mg Mycophenolate Mofetil+ 25-50 mg Cyclosporine. When required additional weekly oral Methotrexate increased efficacy without additional adverse effects.

Remission is defined when the ESR is < 25 mm/1 hour, the mean Systemic Lupus Activity Measurements (SLAM) Score is < 1, and the 24 hours urinary Micro-Albumin is normal. Histological normalization of renal biopsy is obtained when Remission without Drug is achieved. There are 5 other valid outcome measures for Lupus.

Tapering off Intravenous and Oral Therapy
Declining ESR levels to < 40, < 30, and < 25 mm/hour (men minus 10 mm), the 5X weekly daily intravenous sessions of Cyclophosphamide + Methylprednisolone is reduced to 3X, 2X, and 1X weekly respectively. When the ESR is < 25 mm (men < 15 mm) and SLAM Score < 1, Remission with Intravenous Therapy is achieved. Then the intravenous sessions are tapered to once fortnightly, once 4-weekly, once 8-weekly, and terminated to Remission with oral Drugs. When the intravenous therapy is tapered to once fortnightly, the intravenous MTX is switched to a weekly equivalent oral dose.

Remission with oral Drugs must be consolidated with oral Immunosuppressants for at least 2 years. Thereafter, oral drugs are tapered off over a period of 1 year to Remission without Drug (FDA terminology). Flare during tapering off intravenous and oral sessions, Remission with oral Drugs, and Remission without Drug is immediately suppressed by re-installment of the National Institute of Health recommendation.

Flare is defined when the ESR rises to > 25 mm and the SLAM Score > 1.

When diabetes mellitus, corticosteroid-induced hyperglycemia, a history of melena and hematemesis, intravenous Methylprednisolone cannot be given. Empirically, intravenous
5-Fluorouracil replaces Methylprednisolone.

The Step-down Bridge Protocol of Intravenous and Oral Combination of 6 Immunosuppressants is in fact 5 drugs minus Methylprednisolone. The 5 Immunosuppressants combination minus Methotrexate is identical to the National Institute of Health recommendation for the treatment of Lupus Nephritis.

The National Institute of Health recommendation for therapy of Lupus Nephritis is similar to the reversal of the American College of Rheumatology Pyramid System for treatment of RF+ RA: intravenous Methylprednisolone+Cyclophosphamide + oral Mycophenolate Mofetil+Cyclosporine. This is simiar to the Step-down Bridge Protocol of Intravenous and Oral Combination of 5 Immunosuppressant minus intravenous Methotrexate: intravenous Methylprednisolone+Cyclophosphamide+ Methotrexate + oral Mycophenolate Mofetil+Cyclosporine

Analysis of over 10 years observation concludes that Remission without Drug is achieved in Immunosuppressant-naïve Lupus Nephritis patients with Chronicity Index of < 5. In those Immunosuppressant non-naïve Lupus Nephritis patients long-term Remission with oral Drugs is obtained.

Immunosuppressants-naivety (IMN-naivety) in Lupus Nephritis
Besides Chronicity Index of < 5, IMN-naivety is one of the determinants for the outcome of therapy in Lupus Nephritis treated with the Step-down Bridge Protocol of Intravenous and Oral Combination of 5 immunosuppressants (SBP-5-IMNs or S5Is).

Intravenous (IV) IMN-Naivety is defined as no previous exposure to the 4 IMNs comprising Methylprednisolone (MPS), Methotrexate (MTX), Cyclophosphamide (CyC), and 5-Fluorouracil (5FU) by IV administration.

Intravenous IMN non-naivety
One-fourth IV IMN non-naivety is defined as previous exposure of the patient to one of the four IMNs parenterally.
Half IV IMN non-naivety is defined as previous exposure of the patient to two of the four IMNs parenterally.
Three quart IV IMN non-naivety is defined as previous exposure of the patient to three of the four IMNs parenterally.
Total IV IMN non-naivety is defined as previous exposure of the patient to all of the four IMNs parenterally.

Oral IMN-naivety is defined as no previous exposure of the patient to all three oral IMNs comprising Mycophenolate Mofetil (MMF), Cyclosporine (CyS), and MTX

One-third oral IMN non-naivety is defined as previous exposure of the patient to one of the three oral IMNs.
Two third oral IMN non-naiveties is defined as previous exposure of the patient to two of the three oral IMNs
Total oral IMN non-naivety is defined as previous exposure of the patient to all three oral IMNs.

Save for oral Mycophenolate Mofetil, the generic intravenous Cyclophosphamide, Methylprednisolone, Methotrexate, 5-Fluorouracil, and oral generic Cyclosporine all are available free of charge from the Health Insurance (ASKES). Lupus Nephritis patients who are eligible for reimbursement should claim these immunosuppressants from ASKES.

Pilot open studies in Shanghai, China, and Semarang, Indonesia, observes Remission with intravenous Therapy, Remission with oral Drugs, and Remission without Drug achieved after 2-4 months, 5.5-7.5 months, and 42-54 months respectively since initiation of treatment.

These excellent results of the treatment of Lupus Nephritis with the Step-down Bridge Protocol of Intravenous and Oral Combination of 5 Immunosuppressants warrant scientific prove or Randomized Controlled Trial at international rheumatology centers.
 

  Email This Page   Print This Page