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).