Initial management in suspected PNP/PAMS

The varied clinical presentations of PNP/PAMS supports the need for patients who present with an aggressive mucous membrane and/or cutaneous eruption, with overlapping features of pemphigus vulgaris, erosive lichen planus, or erythema multiforme, to be assessed for the possibility of PNP/PAMS prior to the institution of empirical immunosuppressive therapy. Empirical immunosuppression in the setting of an undiagnosed neoplasm may be highly detrimental to the patient’s clinical condition, particularly as one hypothesis regarding the pathogenesis of PNP/PAMS involves direct production of autoantibodies by tumor cells. Similarly, in individuals presenting with a known history of neoplastic disease, caution should be exercised in empirical immunosuppression prior to definitive diagnosis, and a reduced threshold for bladder IF testing should be considered.

In the acute inpatient setting, stabilization of the patient is paramount while identification of the suspected neoplasm, or assessment of the progression of a known neoplasm, occurs. Previous empirical immunosuppression may already have been initiated before the identification of a neoplasm, and this should be taken into account when assessing the need for monitoring and other supportive therapy, as sepsis may cause rapid and life-threatening deterioration. This deterioration is another reason why suspected cases of pemphigus are best managed in a specialist center familiar with autoimmune bullous diseases, of which there are a few in most countries.

Management strategies in PNP/PAMS

Management strategies in PNP/PAMS can be divided into a series of 6 steps, which should begin when PNP/PAMS is suspected as a diagnosis:

• 1.
  

  Stabilization of the patient

  
  
• 2.
  

  Investigation for the presence of malignancy

  
  
• 3.
  

  Establishment of a definitive diagnosis of PNP/PAMS

  
  
• 4.
  

  Removal of the underlying neoplasm where feasible

  
  
• 5.
  

  Medical treatment of the underlying neoplasm

  
  
• 6.
  

  Treatment of the disease itself (individualized for the patient) through either:

  
  
  
  
  • a.
    

    Immunosuppression

    
    
  • b.
    

    Immunomodulation

    
    
  • c.
    

    Removal of pathogenic autoantibodies.

  
  

The most definitive management of PNP in cases involving localized nonmetastatic neoplasm involves the elimination/removal of the causative neoplasm, although in many cases the high and rapid progression to mortality in PNP/PAMS results in the acute management and stabilization of the patient to be of greater immediate priority than definitive surgical or oncologic therapy. In cases of PNP/PAMS that have been associated with thymoma or Castleman tumor, surgical excision of the tumor has been shown to radically improve the cutaneous manifestations of the illness, although a few reports have shown persistent disease despite the elimination of the underlying neoplasm.

As opposed to other forms of pemphigus, for which high-dose corticosteroids and immunosuppressive agents have a moderate success rate in reducing the severity of the disease, many cases of PNP/PAMS have been reported to be resistant to all forms of therapy as traditionally used in other autoimmune bullous diseases. This high level of resistance to therapy supports several of the mechanisms as presented by Vezzoli and colleagues, who suggest that the tumor cells either directly produce the autoantibodies as seen in PNP/PAMS (also seen in malignant acanthosis nigricans), or are indirectly involved in their production or activation. Other contributing factors to the relatively large number of reports of resistant cases may be publication bias, as well as the knowledge that the success of treatment in PNP/PAMS is dependent on many complex and interacting factors, including the length of survival of the patient, the progression of underlying malignancy, and other cormorbidities such as concurrent infection secondary to immunosuppression from previously unsuccessful therapies. Many patients who may be successfully treated with particular therapies may not survive long enough to see the outcome, secondary to their underlying malignancy or sepsis. This aspect reiterates the importance of further investigation into the underlying pathophysiology of PNP/PAMS in order to correlate the mechanisms underlying the disease process with successful treatment modalities.

Management strategies in PNP/PAMS

Management strategies in PNP/PAMS can be divided into a series of 6 steps, which should begin when PNP/PAMS is suspected as a diagnosis:

• 1.
  

  Stabilization of the patient

  
  
• 2.
  

  Investigation for the presence of malignancy

  
  
• 3.
  

  Establishment of a definitive diagnosis of PNP/PAMS

  
  
• 4.
  

  Removal of the underlying neoplasm where feasible

  
  
• 5.
  

  Medical treatment of the underlying neoplasm

  
  
• 6.
  

  Treatment of the disease itself (individualized for the patient) through either:

  
  
  
  
  • a.
    

    Immunosuppression

    
    
  • b.
    

    Immunomodulation

    
    
  • c.
    

    Removal of pathogenic autoantibodies.

  
  

The most definitive management of PNP in cases involving localized nonmetastatic neoplasm involves the elimination/removal of the causative neoplasm, although in many cases the high and rapid progression to mortality in PNP/PAMS results in the acute management and stabilization of the patient to be of greater immediate priority than definitive surgical or oncologic therapy. In cases of PNP/PAMS that have been associated with thymoma or Castleman tumor, surgical excision of the tumor has been shown to radically improve the cutaneous manifestations of the illness, although a few reports have shown persistent disease despite the elimination of the underlying neoplasm.

As opposed to other forms of pemphigus, for which high-dose corticosteroids and immunosuppressive agents have a moderate success rate in reducing the severity of the disease, many cases of PNP/PAMS have been reported to be resistant to all forms of therapy as traditionally used in other autoimmune bullous diseases. This high level of resistance to therapy supports several of the mechanisms as presented by Vezzoli and colleagues, who suggest that the tumor cells either directly produce the autoantibodies as seen in PNP/PAMS (also seen in malignant acanthosis nigricans), or are indirectly involved in their production or activation. Other contributing factors to the relatively large number of reports of resistant cases may be publication bias, as well as the knowledge that the success of treatment in PNP/PAMS is dependent on many complex and interacting factors, including the length of survival of the patient, the progression of underlying malignancy, and other cormorbidities such as concurrent infection secondary to immunosuppression from previously unsuccessful therapies. Many patients who may be successfully treated with particular therapies may not survive long enough to see the outcome, secondary to their underlying malignancy or sepsis. This aspect reiterates the importance of further investigation into the underlying pathophysiology of PNP/PAMS in order to correlate the mechanisms underlying the disease process with successful treatment modalities.

Corticosteroids

Corticosteroids are usually considered a first-line therapy for PNP/PAMS ; however, in the majority of cases the disease progresses or fails to remit despite the use of pulsed and high-dose steroid regimens. While the majority of case reports demonstrate a positive effect of corticosteroids on the cutaneous manifestation of the illness, there is typically little improvement in the stomatitis, which many investigators report to be poorly responsive to a variety of therapies. Vezolli and colleagues specifically comment that one of the clinical hallmarks of PNP is the resistance of the mucosal lesions to most therapeutic strategies. Case reports do exist as to the efficacy of steroids alone in PNP, usually in non-Hodgkin’s lymphoma with relatively mild mucosal involvement. This indication may be of a more benign form of PNP, which would be more responsive to steroids as a monotherapy. High-dose corticosteroids are still recommended as the first line of treatment because they have some degree of efficacy, particularly for cutaneous lesions.

Systemic corticosteroids are also used alongside other chemotherapy agents including azathioprine, cyclosporine, and mycophenolate mofetil, although response rates vary dramatically depending on the underlying neoplasm and combination of agents used. Similarly to corticosteroids alone, although improvement is commonly seen in the cutaneous lesions of PNP, the mucous membrane involvement is particularly resistant to treatment.