Patients with complex dermatoses such as pyoderma gangrenosum, cutaneous lupus, and B-cell disorders, such as pemphigus, may present unique management challenges. These conditions may greatly affect patients’ quality-of-life and social functioning, and many present for specialized care after years or even decades of ineffective treatments. Helping these patients may require use of advanced systemic therapies. George F. Cohen, associate clinical professor and Dermatology Residency program Director, Florida State University, USA described the rationale for using rituximab, thalidomide, and anti-tumor necrosis factor (TNF) inhibitors, sometimes outside the approved label, keeping in mind the best interests of your patients.
According to FDA guidance, physicians can use a product for a none approved labeling, as long as they are well informed about the product, base its use on firm scientific rationale and on sound medical evidence, and maintain records of the product's use and effects. When considering off-label use, patients should be informed of the risks and benefits, alternatives, and limitations associated with off-label use, and provide informed consent. Patients must be active partners in surveillance, and agree to laboratory monitoring as needed, and report any adverse effects back to the physician.
Rituximab is a monoclonal antibody (mAb) directed against the pan-B cell antigen CD20. It is a chimeric antibody; that is, part human, part mouse antibody. Because CD20 is a pan-B cell antigen, rituximab targets all B cells, including good ones, malignant ones, and those producing antibodies. This makes it suited for B cell malignancies and autoimmune and inflammatory conditions triggered by B cells. Three mechanisms are at play with rituximab: antibody-dependent cell-mediated cytotoxicity, leading to cell lysis; complement activation, which marks target cells for killing by effector cells; and apoptosis.
Serious, sometimes fatal infusion reactions, including anaphylactic shock can occur, which may be associated with antibodies triggered by the murine moiety. Thus, rituximab is best administered in an infusion center. The patient should be pretreated with diphenhydramine, methylprednisolone, and acetaminophen. It is administered in a saline IV. Epinephrine and other medications used in advanced cardiac life support should be readily available.
Cohen shared examples of cases in which rituximab was used to successfully treat patients with troublesome and disfiguring cases of pemphigus vulgaris and pemphigus foliaceous, as well as some blistering diseases, including patients who had not responded to large doses of systemic steroids or intralesional steroids.
Thalidomide may provide another avenue of treatment for some complex dermatoses. Thalidomide is a much-maligned drug, due to its association with birth defects in the 1950s and 1960s after it was improperly used in pregnant women to prevent morning sickness. Now it is valued for its array of biological effects such as its use as an anti-TNF and anti-inflammatory, decreasing chemotaxis and phagocytosis, and it is antiangiogenic and antineoplastic. It was approved in 1998 for erythema nodosum leprosum (ENL), a type 2 reaction to leprosy mediated by antibody-antigen reactions associated with inflammation and nerve damage, and later to treat myelodysplastic syndromes. Newer derivatives of thalidomide are also available.
Thalidomide is given orally, and the patient must be enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program. Only 28 days of medication can be dispensed at a time. Lower grade neuropathy may occur, which resolves after treatment is discontinued. Two common side effects are constipation and drowsiness, which can be easily managed.
In addition to on-label use in ENL, Cohen has also successfully used thalidomide off-label to manage prurigo nodularis and discoid lupus erythematosus (DLE), noting that in the latter case it can resolve disfiguring lesions, help patients re-pigment, and provide relief for painful palmar lesions. Other off-label uses of thalidomide include graft-vs-host related mucositis and intractable aphthous stomatitis that may accompany infection with human immunodeficiency virus (HIV).
He also described his experience with on-label and off-label use of anti-TNF drugs, including adalimumab and infliximab. Adalimumab is a fully humanized mAb approved for multiple rheumatologic indications, as well as plaque psoriasis and hidradenitis suppurativa, and may have off-label applications for other dermatologic diseases. Patients should be tested for tuberculosis, hepatitis B, HIV, and other infections before receiving adalimumab. Because adalimumab can cause antinuclear antibody (ANA) induction, ANA titers should be measured prior to treatment, to help identify new changes in ANA.
Cohen has successfully treated patients with pyoderma gangrenosum with the psoriatic dose of adalimumab (80 mg administered subcutaneously on day 1, 40 mg a couple of weeks later, and then 40 mg every 2 weeks). Some of these patients have had complex medical histories and comorbidities, including underlying rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, and postsurgical pyoderma gangrenosum, and failed treatment with high doses of corticosteroids and/or antibiotics. He reports remarkable improvement with anti-TNF therapy in these patients, noting that lesions on the lower extremities may take longer to heal.
In more complicated and intractable cases, he has used adalimumab or infliximab in combination with thalidomide and cyclosporine.
Other situations in which Cohen has used anti-TNF agents include dissecting cellulitis and carpal tunnel syndrome associated with psoriasis.