Wednesday, December 19, 2018

Pemphigus Vulgaris in a 43 yo Woman

The patient is a 43 yo Hispanic female. with several months of bleeding gums, sloughing tissue, and generalized oral pain.   She is otherwise healthy and takes no meds or supplements.  She has no skin or vaginal lesions.

Lab: Normal CBC and metabolic panel.

Her oral surgeon did a biopsy biopsy of normal mucosa adjacent to sloughing attached gingiva on anterior mandible and sent this for direct immunoflouresence (DIF).

Clinical Image:

H&E: Acantholysis
DIF:  Intercellular deposition of C3 and IgG.

Diagnosis: Pemphigus vulgaris

This patient does not live close to an academic center and travel there would be difficult.
Does it make sense to initiate therapy with rituximab (if her insurance covers that) + prednisone. or should therapy be initiated with prednisone and conventional  adjunctive added later if nexessary?


1. 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.
Joly P. et. al.   Lancet. 2017 May 20;389(10083):2031-2040.
This is a paper by the French study group on autoimmune bullous skin diseases.
CONCLUSIONS: 32.5% of our patients with moderate to severe pemphigus vulgaris failed prednisone and traditional CAT treatment and required rituximab therapy. Rituximab reduced the monthly prednisone intake in these patients by 73%. This suggests that a subset of patients with moderate to severe pemphigus may benefit from early institution of rituximab therapy. Rituximab significantly reduces the monthly prednisone requirement among CAT-resistant pemphigus vulgaris patients to levels on par with CAT-responsive patients.

2. Comparison of rituximab and conventional adjuvant therapy for pemphigus vulgaris: A retrospective analysis.
Agarwal A, Hall RP 3rd, Bañez LL, Cardones AR.
PLoS One. 2018 Sep 25;13(9):e0198074.  Free PMC Article
CONCLUSIONS: 32.5% of our patients with moderate to severe pemphigus vulgaris failed prednisone and traditional CAT treatment and required rituximab therapy. Rituximab reduced the monthly prednisone intake in these patients by 73%. This suggests that a subset of patients with moderate to severe pemphigus may benefit from early institution of rituximab therapy. Rituximab significantly reduces the monthly prednisone requirement among CAT-resistant pemphigus vulgaris patients to levels on par with CAT-responsive patients.

JAMA Dermatol. 2015 Aug;151(8):878-82.
Intralesional Rituximab in the Treatment of Refractory Oral Pemphigus Vulgaris.
Vinay K, Kanwar AJ, Mittal A, Dogra S, Minz RW, Hashimoto T.
JAMA Dermatol. 2015 Aug;151(8):878-82.
Oral lesions of pemphigus vulgaris are usually recalcitrant and respond slowly to treatments. Corticosteroid injection is considered to be the most effective local treatment in oral pemphigus vulgaris. However, intralesional corticosteroids are not effective in all remnant lesions. In 3 such patients with pemphigus vulgaris, we evaluated the utility of 2 injections (on days 1 and 15) of intralesional rituximab, 5 mg/cm², in terms of accelerated healing, limitation of the use of systemic immunosuppressants, and reduction of their adverse effects.
Three patients (1 man and 2 women) received 2 doses of intralesional rituximab in March and April 2013. All 3 patients responded to the treatment. In patients 1 and 2, the objective severity score was reduced to 0 at the final visit from a baseline score of 4 and 5, respectively (range, 0-11). The subject severity score in these patients was reduced to 1.0 and 0 from a baseline score of 22.0 and 22.5, respectively. After clinical remission was achieved, patient 3 developed a relapse of mucosal lesions. At the final visit, all of the patients were satisfied with the treatment, with a mean satisfaction score of 8 (maximum score, 10). We found a marked decline in the CD19 cell count from a pretreatment mean count of 287 cells/µL to 6 cells/µL on day 15 after a single intralesional rituximab injection. Adverse events were limited to local pain in 1 patient.
Intralesional rituximab administration lacks the adverse effects of intravenous administration. This method reduces the amount of drug administered and therefore is less expensive. Encouraging results from our study should prompt further evaluation of this novel route of rituximab administration in patients with refractory oral pemphigus vulgaris.


  1. Start prednisone while you submit PA for rituxan - it will take a few weeks to get insurance coverage/infusion center squared away anyways. For longer term control the gold standard is certainly Ritux if it is covered/possible.

  2. Robert Shapiro: "No steroids , just rituximab and IVIG"

  3. Khalifa Sharquie, Baghdad: Steroid and azothioprine saved the life of hundreds of patients with pemphigus over years as the disease is endemic in Iraqi population affecting young patients .Rutiximap is rarely available and expensive.

  4. Thanks for the consultation.
    I'd start with oral washes with topical steroid, and azathioprine PO,

  5. Richard Sontheimer wrote: "Since moving to Utah, I haven’t cared for many autoimmune blistering disease patients since we have several other people in our department who have a subspecialty interest and do research in this area, including our departmental Chairman, John Zone. On several occasions John has told the derm faculty that if he ever personally develops pemphigus he wants to be treated with rituximab first rather than prednisone. I think he was half joking about this but also half serious.

    It is my understanding that while some pemphigus patients respond extremely well to rituximab-induced B-cell depletion, others do not. The same has been true for systemic LE and dermatomyositis. It has been difficult to understand these marked inter-individual differences in clinical response rates.

    I gave a grand rounds presentation in our department this past summer during which I presented a review of some preliminary data from the rheumatology literature suggesting that the clinical impact of rituximab on otherwise-refractory SLE nephritis might be markedly enhanced by sequential belimumab (Benlysta) subcutaneous injections following B-cell depletion with IV rituximab. The rationale is that belimumab might prevent the rebound wave of B-lymphocyte stimulator (BLyS) (syn. B cell activating factor [BAFF]) that occurs after rituximab induced B-cell depletion. Thus, this combination therapy might produce a longer period of B-cell-induced autoimmune suppression. There are now ongoing clinical trials to formally test this hypothesis in SLE nephritis. I have attached a PowerPoint file containing the relevant slides from my Grand Rounds presentation.

    If this proves to be true it may have a value other B-cell mediated autoimmune disorders including dermatomyositis and pemphigus/pemphigoid.

    All things being equal (including affordability of the rituximab), I would strongly consider starting the VGRD pemphigus patient on rituximab and prednisone with the idea of tapering the prednisone to a safe low dose range as the rituximab induced B-cell depletion kicked in clinically."

  6. Henry Foong, Ipoh, Malaysia. wrote:"I had a similar patient in 2018 referred to me by an ENT surgeon. A chinese woman in her 50s with recurrent ulcerations and blisters in the buccal mucosa esp upper hard palate. Biopsy confirmed pemphigus vulgars. I treated her with oral prednisolone and weekly methotrexate and she achieved remission. Now she is on prednisolone 10mg daily and methotrexate 7.5 mg weekly with topical triamcinolone gel when necessary. I have stopped using azathioprine as the response is slow and inadequate. I find methotrexate much better in terms of efficacy. Rituximab is too expensive in our practice and not sure if warranted in such limited oral disease."

  7. Jorge Roman, NYU Skin and Cancer: "What's interesting about NYU is that the treatment would vary depending on which attending the patient saw. Some are a little more conservative with oral steroids while others have a lower threshold. The burden of pemphigus on the patient is an important factor to consider. If she's unable to eat comfortably and losing weight, prednisone might be more favorable at least in the interim while rituxan gets approved. If rituxan isn't an option, cellcept seems to be the go to choice for most of the faculty here. If a patient does not get improvement with max dose of cellcept, adding on dapsone usually does the trick. IVIG can also be considered but given the patient is far from an academic center, likely not feasible for her."

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  9. From Professor John Zone: "I have given a lot of thought over the years to the treatment for bullous disease and the complications associated with these treatments. I can unequivocally say that the vast majority of the severe side effects that I have seen have been caused by systemic corticosteroids. So, I have asked myself frequently “what would I do if I had……”. I have given a talk nationally on multiple occasions entitled “what would I do if I had pemphigus”. There is absolutely no doubt in my mind that I would take rituximab as a first-line therapy. It has relatively few side effects when given properly and monitored. I would be vaccinated for zoster, pneumococcal pneumonia and DPT, before I took the rituximab. The real question then becomes what I would do while I was waiting the 60 to 90 days for rituximab to have its effect. I think I would take pulse IV Solu-Medrol monthly, since it is more effective and has fewer side effects than oral prednisone. I would probably take CellCept if I had a lot of disease activity.

    Remember, the only FDA approved therapy for pemphigus is Rituxan. Since it has been approved by the FDA, it has been very difficult for any insurance company to refuse this approved treatment for potentially fatal disorder."

  10. From Christopher Hull (U of Utah): "Christopher Hull

    Wed, Dec 26, 9:45 PM (7 hours ago)

    to Richard, John, me
    Depending on severity, medical history, antibody titers etc, would strongly recommend rituximab. Our experience the past 15+ years has shown it to be the most effective medication. The Lancet paper last year supports it as 1st line therapy, and clearly superior to prednisone. It is also now FDA approved for pemphigus. Coordinating the infusions can be a little confusing if you haven't done this before (some Heme/Onc or rheum providers are willing to help). Genentech has a generous patient support program in the event that someone is either uninsured or insurance unwilling to cover. "


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