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B cells and auto antibodies in the pathophysiology and treatment of pemphigus vulgaris pemphigus vulgaris is a b-cell-mediated autoimmune disease characterized by the production of pathogenic autoantibodies directed against desmoglians proteins responsible for cell adhesion in the epidermal layer of the skin these autoantibodies cause loss of cell adhesion in
The skin and mucous membranes the etiology is unknown but b cell activation and differentiation give rise to auto antibody producing memory b cells and plasma cells auto antibodies in pemphigus vulgaris target desmiglian3 and desmoglion1 that function in desmosomes in the suprabasilar keratinocytes in the skin and mucus membranes what’s unique about pempagus
In comparison to several other autoimmune conditions is the antibodies are thought not to be just a marker of the disease but actually to cause the disease without needing complement activation two mechanisms are thought to be responsible the first is steric hindrance where the binding of the antibodies disrupt the adhesion between keratinocytes so they fall
Apart and the second is through an intracellular cascade of events which cause the cytoskeleton within the keratinocyte to break down so that the cells shrink and pull apart from each other the disruption of cellular adhesion results in acantholysis and characteristic blister formation these blisters are flaccid and rupture easily leaving behind painful erosions
A positive nikolsky sign where blisters rupture easily with mild lateral pressure is suggestive of pemphigus bulgaris and an indication for biopsy pempagus vulgaris most frequently presents in the mouth but may also involve other mucosal surfaces as well as the skin histologic and serologic testing are necessary to confirm the diagnosis of pemphigus vulgaris
Although a positive nikolsky sign is indicative of pemphigus vulgaris additional testing is needed histology using h e staining is the first test to definitively diagnose pemphigus vulgaris this is done with a biopsy of paralegianal tissue or of a small intact vesicle present less than 48 hours h e staining shows characteristic acantholysis from disruption of
The cellular adhesions serologic testing is used to show the presence of antidesmigley and antibodies this is done with either immunofluorescence staining or elisa direct immunofluorescence is used to show the presence of autoantibodies in a biopsy of paralegianal tissue fluorescently labeled antibodies tagged the pathologic anidesmaglian antibodies showing
The presence of igg and c3 in a net like pattern within the lower epidermis anidesmoglian antibodies in the blood can also be assessed by indirect immunofluorescence or elisa for indirect immunofluorescence serum is incubated in a tissue substrate any desmoglian antibodies if present will bind to the tissue substrate and can be tagged by a fluorescent marker
Elisa is a serologic test to measure specific anti-desmoglian antibodies in blood serum anidesmicleon if present bind to substrate in a well and are tagged by a colorimetric marker so that the titer can be measured the high sensitivity and specificity and increased availability of these tests has increased their utilization in addition serologic testing can also
Be helpful monitoring the response to therapy once the diagnosis of pemphigus vulgaris has been confirmed assessing disease severity helps determine therapy there are currently no accepted cutoff values to define disease severity it can be mild moderate or severe there are two scoring assessments used in clinical trials these factor both the extent of involved
Area and lesion quality the goals of therapy are to promote healing of blisters and erosions improve functional status reduce the development of new blisters and erosions improve the quality of life and limit common side effects associated with long-term immunosuppressive or corticosteroid therapy corticosteroids are the backbone of the pemphigus vulgaris therapy
Corticosteroids quickly suppress inflammation reducing b cell levels and auto antibody titers patients with early mild and or orally limited disease may be successfully managed with topical steroids those with more extensive involvement will require systemic immunosuppressive therapy in addition to corticosteroids corticosteroids have improved overall mortality
From 75 percent before the advent of corticosteroids to the current less than 30 percent most of the current morbidity and mortality relates to the adverse effects of therapy particularly infections and cardiovascular disease the side effects of corticosteroids depend on the length of usage because of these steroid side effects corticosteroids are tapered once
The patient has responded meaning existing lesions have begun to heal and no new lesions have developed the objective should be to achieve as rapid a remission as possible as few flares as possible and minimal morbidity associated with treatment agents complete remission on therapy is defined as the absence of new or established lesions for at least two months
While the patient is receiving minimal therapy steroid sparing agents are recommended in pempagus vulgaris rituximab is an anti-cd20 monoclonal antibody that has been fda approved as the first targeted immunosuppressive therapy for pemphigus vulgaris cd20 is present on b cells including mature naive and memory b cells but not on differentiated plasma cells
Rituximab causes a selective transient depletion of cd20 positive b cells thereby reducing auto antibody titers in pempagus because plasma cells do not carry the cd20 marker not all antibody production is suppressed meaning serum antimicrobial igg titers remain stable it has been hypothesized that short-lived plasma cells are responsible for producing the bulk
Of pathogenic auto antibodies responsible for disease in pempace clinical trials of rituximab administered with corticosteroids two patients with pemphigus vulgaris have demonstrated greater efficacy compared with steroids alone or steroids plus mycophenolate in the ritux3 trial patients with newly diagnosed pemphigus were randomized to receive either oral
Prednisone alone tapered over 12 or 18 months or rituximab on day 0 and 14 12 in 18 months combined with short-term prednisone tapered over three or six months the primary endpoint was rate of remission off therapy at 24 months at month 24 41 of 46 or 89 percent of patients randomized to rituximab plus short-term prednisone were in complete remission off therapy
Compared to only 15 of 44 or 34 assigned to the prednisone only group rituximab is more than 2.5 times more likely to result in remission with the number needed to treat less than two patients receiving rituximab achieved complete remission off therapy significantly faster than those receiving prednisone alone those in the rituximab group had a significantly longer
Time in remission the relapse rate for patients receiving rituximab was less than those receiving prednisone and 75 percent of patients receiving rituximab achieved two-year disease-free survival compared with only 37 percent of patients receiving prednisone alone additionally in the third year of follow-up of the patients who achieved complete remission off therapy
At 24 months only one patient representing two percent of the rituximab group experienced the relapse in year three compared with four of 15 patients or 27 percent in the prednisone group who experienced relapse in year three total and desmoglian specific b cells were eliminated by rituximab but numbers remained unchanged in the prednisone group anti-desmoglian
Antibody titers decreased similarly for both groups in the first 12 months but rebounded to deductible levels at 24 months only for the group receiving prednisone alone a second endpoint was the difference in cumulative steroid dose patients receiving rituximab used nearly one-third of the amount compared with the prednisone group and patients receiving rituximab
Had greater improvements in quality of life scores than those receiving prednisone alone more patients discontinued the study from the prednisone alone group due to treatment failure and treatment-related adverse events similarly severe adverse events were about twice as common among those receiving prednisone alone than those receiving rituximab the most common
Serious adverse events were diabetes and endocrine disorders myopathy and bone disorders the infection rates were similar among both groups the ritux3 trial demonstrated the safety and efficacy of including rituximab in first-line therapy for pempagus for bringing about complete remission and allowing for a more rapid steroid taper than the standard of care
Another recent randomized controlled trial pemfix compared the use of rituximab with the steroid sparing agent mycophenolate mofatel in pemfix rituximab and mycophenolate were both used in combination with prednisone and a short-term steroid taper in patients with a new diagnosis of pempagus vulgaris to assess for complete remission and disease-free survival over
52 weeks of treatment 135 patients were randomized 67 to rituximab and 68 to mycophenolate 40 of patients receiving rituximab achieve sustained complete remission off therapy at 52 weeks which was superior to the 9.5 percent of patients receiving mycophenolate patients receiving rituximab had a significantly lower cumulative steroid dose as well as a lower median
Daily dose rituximab was associated with significantly fewer disease flares and fewer patients experiencing disease flare patients in the rituximab arm were nearly five times more likely to achieve sustained complete remission off therapy and about seven times less likely to experience a flare compared with those in the mycophenolate arm rituximab was associated
With significantly greater improvements in the dlqi compared with mycophenolate rituximab was associated with a numerically greater infection rate and rate of infusion reactions corticosteroid adverse events were similar for both the rituximab and mycophenolate group but numerically higher for the mycophenolate group the pemfix study establishes the superiority
Of rituximab over mycophenolate in the treatment of pemphigus vulgaris other agents such as azathioprine mycophenolate cyclophosphamide an ivig can be used to suppress the immune system in pemphigus vulgaris azathioprine has steroid sparing effects and can be used in combination with prednisone for control in early disease or as maintenance therapy mycophenolate
Can be combined with prednisone for treating early disease or can be used after initial treatment for pemphigus vulgaris cyclophosphamide is generally reserved for patients who do not respond to other immunosuppressives for pemphigus due to the side effect profile associated with cyclophosphamide measures to reduce high titers of anti-desmoglian antibodies include
Ivig immunoabsorption plasmophoresis and plasma exchange these have been described as effective in severe pemphigus vulgaris patients for controlling disease activity by reducing serum levels of autoantibodies but these are not immunosuppressive the primary objective of the therapeutic management of pemphigus vulgaris is initially to control the disease heal the
Bullish skin and mucosal lesions and minimize the associated functional impairments in addition to immunosuppressive therapy wounds care and oral hygiene measures are important to relieve pain reduce infection and foster healing of pemphigus vulgaris lesions in the case of relapsed pemphigus vulgaris options include increasing or restarting steroids adding an
Immunosuppressant or replacing the first-line immunosuppressant with another if already on combination therapy the weight-based lymphoma dosing protocol for rituximab may be beneficial for relapsed or resistant disease subsequently the real challenge is to prevent relapses and reduce adverse events associated with the prolonged use of steroids and immunosuppressive
Agents this requires close clinical monitoring of patients over long-term therapy in summary pemphigus vulgaris is an auto antibody mediated condition that responds well to immunosuppressive therapy particularly when detected and treated early currently b cell depletion with rituximab combined with corticosteroid therapy has demonstrated the greatest efficacy for
Inducing remission steroid-sparing agents are necessary to induce and maintain remission and to reduce the adverse effects associated with long-term corticosteroid therapy for discussion of the practical applications of immunosuppressive therapy in pemphigus vulgaris continue to the case discussions
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Strategies For Pemphigus Vulgaris Management | Paradigm Medical Communication By Simply Explainer
