Dr. Sergei Grando shares his multidrug protocol shown to offer potential cure for the majority of pemphigus and pemphigoid patients.
Sergei A. Grando, MD, PhD, DSc, is Distinguished Professor, Department of Dermatology, Department of Biological Chemistry, and Director, Immunobullous Clinic, University of California Irvine, Irvine, California
“Before corticosteroids were introduced in the 1950s, the mortality from pemphigus was 50% within 2.5 years and 100% within 5 years of the disease. …steroids changed the entire field, so patients no longer died from this disease if they were treated in a timely manner before they developed sepsis and other complications,” said Sergei A. Grando, MD, PhD, DSc, who presented “Pemphigus and Pemphigoid,” during the 3rd Annual San Diego Dermatology Symposium.
But steroids alone far from solve the problem, said Dr. Grando, who directs one of the largest centers of excellence in the U.S. treating patients with pemphigus and pemphigoid.
“Another problem is that prednisone, instead of being a friend, becomes a foe. Doctors who don’t have experience treating these patients often either overtreat patients with too much for too long, leading to serious side effects, or they treat [with] too little for a short time and patients relapse.”
“That’s why, unfortunately, mortality to date, which is about 10% on average, stems from complications from treatment rather than from the disease itself,” he said.
Three Treatment Goals
Pemphigus and pemphigoid are similar in that there are three potential targets for therapy, according to Dr. Grando.
- Increase resistance to autoantibodies
- Eliminate autoantibodies
- Prevent autoantibody production
“First of all, there is resistance of skin cells, or keratinocytes, to autoantibodies. It’s not uncommon to have patients with antibodies in the system but no lesions. That means that whatever the damage the antibodies can produce is not sufficient for keratinocytes to detach, which is natural resistance. So, one way to help patients is to increase resistance to autoantibodies.”
“The second is to eliminate autoantibodies. Because if you increase resistance without eliminating autoantibodies they will accumulate and, at some point, they will overcome the natural resistance.”
“The third component is to prevent autoantibody production. If you don’t keep eliminating autoantibody-producing cells, they will be still producing.”
The currently approved FDA protocol for treatment includes rituximab plus prednisone, said Dr. Grando.1
“In this protocol 32% pemphigus vulgaris patients who were in clinical remission off therapy relapsed within 5 years after treatment,1,2 and 50% relapsed within approximately 2 years after discontinuation of treatment,” said Dr. Grando.3
But in the multidrug protocol that Dr. Grando documented in an article published in the International Journal of Dermatology, only 12% of patients who were in clinical remission relapsed within 5 years.4
“That paper was not part of any clinical trial. I am the single author. And that paper summarizes my life-long experience with treating patients with this pathology,” said Dr. Grando.
The paper summarizes clinical outcomes of 123 pemphigus patients treated with the 2-plus year multidrug protocol combining intravenous immunoglobulin (IVIG), an immunosuppressive cytotoxic drug and mitochondrion-protecting drugs from 2007 to 2017.
“The overall complete remission rate of all drugs was 100%, with 12% overall relapse rate. No patients had more than a single relapse,” writes Dr. Grando.
The multidrug IVIG regimen achieved three principal treatment objectives: rapid control of pemphigus symptoms, stable disease remission, and prevention of flares, concluded Dr. Grando.
“These are the components of the multidrug protocol I designed.”
“To achieve resistance of keratinocytes to autoantibodies we use systemic corticosteroids (prednisone taper) and mitochondrion protection with niacinamide (also known as nicotinamide) plus tetracycline-type medications. Then we need to eliminate autoantibodies with IVIG. In the past we would eliminate the autoantibodies by using plasmapheresis or plasma exchange, which is no longer reasonable to use because of the price and the need for hospitalization.”
Finally, the protocol prevents autoantibody production with the use of cytotoxic immunosuppression.
Keratinocyte Resistance to Autoantibodies
Corticosteroids protect keratinocytes from autoantibody attack, according to Dr. Grando, who cited a study published in 2004 in the Journal of Biological Chemistry.5
“Methylprednisolone increased the protein levels of E-cadherin and desmoglein (Dsg) 1 and Dsg 3 by 300%, 180%, and 40% respectively. There is gene expression targeted by steroids that leads to upregulation of adhesion molecules, so antibodies are present but keratinocytes acquire higher resistance,” he said.
“Corticosteroids need to be handled with care. Walter F. Lever, MD, published a very useful manual Lever WF. Pemphigus and Pemphigoid. Springfield: Charles C. Thomas, 1965, in which he gives very specific recommendations that prednisone should be started at 1 mg/kg/day. Use that dose for about 10 days or so, and if it doesn’t start to heal existing erosions or if patients develop new lesions, go up by 30% until the disease is under full control. Patients should have no lesions, epithelialization of existing erosions, and negative Nikolskiy sign. Then you can start tapering in a logarithmic fashion by about 25% of the current dose every 2 to 3 weeks.”
Dr. Grando then described the mitochondria’s role and use of minocycline and niacinamide as part of the protocol.6
“Mitochondrial damage has been demonstrated … in both pemphigus and pemphigoid. We and other authors demonstrated empirically that tetracyclines in combination with niacinamide can protect the mitochondria,” said Dr. Grando.
Autoantibody Elimination, Prevention
IVIG saturates the FcRn receptors, which protect immunoglobulin G (IgG) molecules degradation inside the cell.7 Since both disease-specific and normal IgG antibodies are eliminated but only normal antibodies are replenished from donors’ IgG batches, there is selective drop in the serum level of autoantibodies, he said.
“Selective elimination of autoantibodies may lead to a ‘rebound effect’ [or flare] due to stimulation of autoantibody producing cells. There is a way to address that problem …with coadministration of a cytotoxic immunosuppressor. It was shown that combining IVIG with a cytotoxic immunosuppressor prevents compensatory overproduction of pathogenic autoantibodies triggered via negative feedback by their selective elimination.”8
“You start IVIG usually monthly at 2 g/kg/month for 4 to 5 day-long cycles for about a year. Then, 6 months after systemic steroids were discontinued, you continue IVIG on a taper schedule—first with one cycle at 2 months for 6 months and then one in 3 months, twice. And this goes at the background of the use of an immunosuppressant cytotoxic drug, minocycline (or doxycycline), and niacinamide. The duration of the multidrug treatment is usually about 2 years,” said Dr. Grando.
“There is an alternative protocol where you use rituximab at 375 mg/m2 body surface for a total of 10 times during first 24 weeks of treatment. You use rituximab weekly x 3 for the first 2 months, then once a month for an additional 4 months. That’s along with IVIG 2 g/kg/month. All this at the background of minocycline and niacinamide. Once we finish the 6 months of treatment with rituximab, then we go to an oral cytotoxic immunosuppressor so again the treatment is for two years.”
Outcomes are better with the multidrug protocol compared to treatment with only prednisone and rituximab because of the latter treatment’s inability to selectively suppress production of pathogenic autoantibodies, according to Dr. Grando.
“Rituximab targets all CD20 positive B cells regardless of their relevance to pemphigus vulgaris. The targeting of a disease-specific B cell clone occurs purely by chance and the majority of B cell populations repopulate after treatment with rituximab. Unfortunately, those treated with rituximab usually have a flare about once a year.”
“But if you use IVIG in the multidrug protocol, the IVIG selectively and predictably eliminates pathogenic antibodies because both normal and pathogenic antibodies are cleared at the same rate, and normal antibodies are replenished by normal IgGs in IVIG batches,” he said.
Treatment Duration Key
Maintenance with IVIG and an immunosuppressor should be continued for at least 2 years in expectation that the critical mass of autoreactive plasma cells dies off during this timeframe, according to Dr. Grando.
“If you keep patients lesion free for that long a period of time, there is scientific evidence to suggest that critical mass of autoreactive plasma cells will die off during this timeframe. If patients have a flare, they kind of reset the clock of possible cure …. Then you have to wait for another two years before you can expect stable remission off drugs. And that’s why the current approach with prednisone and rituximab is not really helpful [for a] real chance for cure.”
Disclosure: Dr. Grando reports no relevant conflicts of interest.
References:
- Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031-2040. doi:10.1016/S0140-6736(17)30070-3
- Hébert V, Vermeulin T, Tanguy L, et al. Comparison of real costs in the French healthcare system in newly diagnosed patients with pemphigus for first-line treatment with rituximab vs. standard corticosteroid regimen: data from a national multicentre trial. Br J Dermatol. 2020;183(1):121-127. doi:10.1111/bjd.18563
- Kushner CJ, Wang S, Tovanabutra N, Tsai DE, Werth VP, Payne AS. Factors Associated With Complete Remission After Rituximab Therapy for Pemphigus. JAMA Dermatol. 2019;155(12):1404-1409. doi:10.1001/jamadermatol.2019.3236
- Grando SA. Retrospective analysis of a single-center clinical experience toward development of curative treatment of 123 pemphigus patients with a long-term follow-up: efficacy and safety of the multidrug protocol combining intravenous immunoglobulin with the cytotoxic immunosuppressor and mitochondrion-protecting drugs. Int J Dermatol. 2019;58(1):114-125. doi:10.1111/ijd.14143]
- [Nguyen VT, Arredondo J, Chernyavsky AI, Kitajima Y, Pittelkow M, Grando SA. Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. J Biol Chem. 2004;279(3):2135-2146. doi:10.1074/jbc.M309000200]
- Grando SA. The mitochondrion is a common target of disease pathophysiology in pemphigus and pemphigoid. Exp Dermatol. 2015;24(9):655-656. doi:10.1111/exd.12772
- Grando SA, Rigas M, Chernyavsky A. Rationale for including intravenous immunoglobulin in the multidrug protocol of curative treatment of pemphigus vulgaris and development of an assay predicting disease relapse [published online ahead of print, 2020 Mar 12]. Int Immunopharmacol. 2020;82:106385. doi:10.1016/j.intimp.2020.106385
- Czernik A, Toosi S, Bystryn JC, Grando SA. Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update. Autoimmunity. 2012;45(1):111-118. doi:10.3109/08916934.2011.606452