Therapeutic Synergy, Neutrality, and Antagonism: Combination Treatment in Dermatology

Synergy is an appealing yet somewhat ambiguous concept, useful for its applications in maximizing therapeutic efficacy, minimizing side effects associated with any one treatment, and decreasing the development of drug resistance. Synergy finds relevance in nearly all areas of medicine. Oncology, notably, relies heavily on synergistic principles for the successful treatment of almost all cancers, as very few drug-sensitive cancers are treated with a single chemotherapeutic agent,¹ with definitive treatment of many cancers necessitating a multimodal approach.²Definitions of synergy range from theoretical ideas to complex mathematical models,³ with each version having different strengths and weaknesses. These complicated definitions, including Loewe additivity and Bliss independence, are fascinating mathematical exercises but can be counterproductive when the ultimate goal is to detect if a meaningful therapeutic advantage to combination therapy exists.⁴ Perhaps most applicable to clinical dermatology is the idea of therapeutic synergy put forth by Venditti et al in 1956. Therapeutic synergy is used to describe any increase in efficacy of a multifactorial treatment when compared with any of its individual parts alone.⁵ This definition eliminates the need for dose-dependent pharmacologic models and occasionally invalid mathematical assumptions while addressing the fundamental goals of combination therapy: whether or not the use of multiple therapies is beneficial to the patient.⁶Dermatology relies heavily on combination therapy, but the evidence to support the use of many commonly-used combinations over monotherapy is often lacking. Importantly, even when combination therapy is tested in a clinical trial setting, it is often compared to only one mono-therapeutic control group, rather than 2 control groups representing both components. Therapeutic synergy may be more difficult to determine in dermatologic studies when compared with other fields due to small sample sizes and often qualitative outcome measures. However, it is still important to directly determine the efficacy of combined treatment in clinical trials, as synergy that is mechanistically-postulated or determined in the laboratory may not manifest clinically. Proposed synergistic combinations can even be discovered as antagonistic when tested in a clinical setting: for example, zidovudine and stavudine in the treatment of HIV,⁷ penicillin and erythromycin in the treatment of S. pneumoniae infection,⁸ and ACE inhibitors and angiotensin receptor antagonists in patients with heart failure;⁹ all of which have potential mechanistic synergy, but functional antagonism in actual trials.Here we wish to address the concept of therapeutic synergy in dermatology and discuss some of the evidence behind common combination therapies in 4 different dermatologic diseases: atopic dermatitis, acne vulgaris, psoriasis, and cutaneous lupus erythematosus. In doing so, we hope to encourage further formal investigations and discussion of combination therapy in dermatology.

Atopic Dermatitis (AD) is a chronic, pruritic, inflammatory skin condition that often begins in childhood and can affect patients