Discussion
The present report investigated two cases of generalized morphea that developed and rapidly progressed within a few days after SARS-CoV-2 infection and vaccination, both in individuals with no history of rheumatologic or autoimmune disorders.
Localized scleroderma, also known as morphea, is a dermatologic disorder which leads to loss of elasticity and hardening of the skin. This dermatosis is classified as plaque morphea, generalized morphea, linear scleroderma and deep morphea(14). The generalized form of morphea is defined as skin induration and sclerosis in the form of plaques in at least four anatomic sites, including head-neck, each extremity, anterior trunk, and posterior trunk(14). This condition is quite serious and rapidly progressive, and has an unfavorable outcome(15). Considering the characteristics and pattern of eruptions onset, our cases was considered as cases of generalized morphea.
The pathophysiologic mechanism for morphea is still unknown, however, it seems to be the result of immune activation leading to connective tissue dysregulation(16).
Morphea might be related to some environmental factors such as trauma, radiation, medications, infections and vaccines(17). Borrelia burgdorferi has been the most common infective pathogen reported to be associated with morphea(18). Other infections with probable association include hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), toxoplasma, helicobacter pylori, and human endogenous retroviruses (HERV)(19-25). Recently, we have confronted with cases of morphea following SARS-CoV-2 infection(8, 9). The underlying mechanism might be the virus-induced inflammation which gives rise to immune system activation or cross reaction of the virus and the host skin antigens(26). Skin is among the important organs that is involved in the course of any viral infection, including SARS-CoV-2, as we have demonstrated a wide variety of dermatologic complications in the settings of COVID-19, either as the presenting manifestation or occurring in the course of the infection(1, 26).
On the other hand, we can name Diphtheria-Tetanus-Pertussis (DTP), hepatitis B, BCG, and pneumococcal vaccines among the ones reported to be associated with morphea(27-32). However, most of the aforementioned conditions occurred locally and in the vaccine injection sites, rather than appearing in generalized types(28, 30). Up to the present time, no case of morphea has been reported following SARS-CoV-2 vaccination. Nevertheless, it is expected to detect more cases due to the hyperimmune responses following any vaccines, including those for COVID-19. Due to the temporal relationship between the morphea onset and vaccine injection, and considering the negative laboratory results for infections, rheumatologic and malignant disorders, we attributed the condition of our second case to SARS-CoV-2 vaccination.
It is important to note that morphea can also appear as a component of a systemic autoimmune disorder such as systemic scleroderma, lupus erythematosus, thyroiditis, eosinophilic fasciitis, and biliary cirrhosis(33). Most cases of generalized morphea have been reported in association with positive serologic tests results for autoantibodies, particularly ANA(34). We evaluated both of the patients for autoimmune rheumatologic diseases, autoimmune thyroiditis, HCV and HBV, and IgE levels, none of which turned positive. Moreover, some malignancies have been first presented with cutaneous manifestations, such as morphea(35-37). Accordingly, we performed a thorough work-up to detect any malignancies being presented with morphea as a paraneoplastic sign. Therefore, we attributed the condition to infection and vaccination.
Another important issue is the difficulty in differentiating between generalized morphea and systemic sclerosis clinically. However, the absence of Raynaud phenomenon and sclerodactyly and also the negative results for ANA, Anti-centromere, and AntiScl70 justified our diagnosis, which was confirmed with histopathology(38).
We should take into account that some of the therapeutics utilized for managing COVID-19 can lead to florid cutaneous reactions(39). For example, Stevens-Johnson-like syndrome, acute generalized exanthematous pustulosis and urticarial eruprtions have been reported following hydroxychloroquine, acneiform eruptions and localized scleroderma following ribavirin, and psoriasis, alopecia, cutaneous vasculitis, and lichenoid drug reactions have been observed after receiving interferons(40, 41). Our first patient had received interferon beta-1a for her SARS-CoV-2 infection. There have been rare reports of localized morphea at the site of interferon injection(42); however, no case of generalized morphea has been reported in patients who had received this medication. Nonetheless, we should consider the medications, along with the de novo infection as the precipitating factors of the cutaneous reaction in our first patient.
Topical tacrolimus, methotrexate, systemic steroids, D-penicillamine, mycophenolate mofetil, cyclosporine, imiquimod, and calcipotriol have all been applied in managing morphea(43); however, artificial ultraviolet (UV) radiation or phototherapy has been the most effective and the mainstay of treatment(44).