10.5826/dpc.1204a173
Introduction: Granuloma annulare (GA) has been reported as associated with multiple diseases, mainly diabetes mellitus (DM), thyroid diseases, and dyslipidemia. However, the high prevalence of some of these illnesses makes it difficult to assess whether the association is real or fortuitous. Our objective was to analyse the clinical features of our GA patients and the possible associations.
Methods: This is a retrospective observational study of 225 patients with biopsy-proven GA diagnosed between 2009 and 2019 in a referral university hospital in Barcelona, Spain. Clinical charts were reviewed to obtain clinical data. As a control group we used a random list of 225 patients diagnosed in the hospital's traumatology department in the same period, matched by age and sex.
Results: Diabetes was diagnosed in 40 GA patients (18%) (34 in the control group, 15%) and hypothyroidism in 33 (15%) (22 in the control group 9.8%); the differences were not significant. We also did not detect any association with uveitis, sarcoidosis,  necrobiosis lipoidica, Sweet's syndrome, HIV infection, hepatitis B, or haematological malignancies. We only detected a possible association with hepatitis C (6 GA patients, 2.7%, versus 0 controls, p = 0.03), and hypercholesterolemia  (108 GA patients, 48%, versus 79 controls, 35%, p = 0.007).
Conclusions: The possible pathogenic explanations for the association with hepatitis C and hypercholesterolemia seem unlikely. We consider that the association of GA with other diseases, including hypercholesterolemia and hepatitis C, is doubtful and that it there is no justification rule out possible associated diseases in patients with GA.
text/xml
2160-9381
2173
en
Joaquim Marcoval
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
hypercholestertolemia
Granuloma annulare: a case-control study of possible associated diseases.
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-11-16
2022-10-31
2022-12-01
e2022173
Dermatol Pract Concept
Introduction: Granuloma annulare (GA) has been reported as associated with multiple diseases, mainly diabetes mellitus (DM), thyroid diseases, and dyslipidemia. However, the high prevalence of some of these illnesses makes it difficult to assess whether the association is real or fortuitous. Our objective was to analyse the clinical features of our GA patients and the possible associations.
Methods: This is a retrospective observational study of 225 patients with biopsy-proven GA diagnosed between 2009 and 2019 in a referral university hospital in Barcelona, Spain. Clinical charts were reviewed to obtain clinical data. As a control group we used a random list of 225 patients diagnosed in the hospital's traumatology department in the same period, matched by age and sex.
Results: Diabetes was diagnosed in 40 GA patients (18%) (34 in the control group, 15%) and hypothyroidism in 33 (15%) (22 in the control group 9.8%); the differences were not significant. We also did not detect any association with uveitis, sarcoidosis,  necrobiosis lipoidica, Sweet's syndrome, HIV infection, hepatitis B, or haematological malignancies. We only detected a possible association with hepatitis C (6 GA patients, 2.7%, versus 0 controls, p = 0.03), and hypercholesterolemia  (108 GA patients, 48%, versus 79 controls, 35%, p = 0.007).
Conclusions: The possible pathogenic explanations for the association with hepatitis C and hypercholesterolemia seem unlikely. We consider that the association of GA with other diseases, including hypercholesterolemia and hepatitis C, is doubtful and that it there is no justification rule out possible associated diseases in patients with GA.
Joaquim Marcoval
2022/10/31
10.5826/dpc.1204a173
e2022173
Department of Dermatology, Hospital Universitari de Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain
2160-9381
hypercholestertolemia
en
e2022173
Granuloma annulare: a case-control study of possible associated diseases.
https://dpcj.org/index.php/dpc/article/download/2173/1779
            Granuloma Annulare: a Case-control Study
                 of Possible Associated Diseases
                 Rosa Fornons-Servent1, Andrea Bauer-Alonso1, Clàudia Llobera-Ris1,
                              Rosa María Penín2, Joaquim Marcoval1


1 Department of Dermatology, Hospital Universitari de Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain
2 Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain



Key words: granuloma annulare, diabetes, hypothyroidism, hypercholestertolemia
Citation: Fornons-Servent R, Bauer-Alonso A, Llobera-Ris C, Penín RM, Marcoval J. Granuloma annulare: a case-control study of possible
associated diseases. Dermatol Pract Concept. 2022;12(4):e2022173. DOI: https://doi.org/10.5826/dpc.1204a173
Accepted: January 19, 2022; Published: October 2022
Copyright: ©2022 Fornons-Servent et al. This is an open-access article distributed under the terms of the Creative Commons ­­Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: Dr R. Fornons-Servent, Dr A. Bauer-Alonso, Dr C. Llobera-Ris, and Dr R.M. Penín contributed to data acquisition and review
of the manuscript. Dr J. Marcoval contributed to data acquisition, statistical analysis and redaction of the manuscript.
Corresponding author: Joaquim Marcoval, Department of Dermatology, Hospital Universitari de Bellvitge, c/Feixa Llarga s/n, Hospitalet
de Llobregat, 08907 Barcelona, Spain, Tel: +34 93-260-7577 Fax: +34 93-260-7844. E-mail: jmarcoval@bellvitgehospital.cat




  ABSTRACT             Introduction: Granuloma annulare (GA) has been reported as associated with multiple diseases,
                       mainly diabetes mellitus (DM), thyroid diseases, and dyslipidemia. However, the high prevalence of
                       some of these illnesses makes it difficult to assess whether the association is real or fortuitous.
                       Objectives: Our objective was to analyze the clinical features of GA patients and the possible associations.
                       Methods: This is a retrospective observational study of 225 patients with biopsy-proven GA ­diagnosed
                       between 2009 and 2019 in a referral university hospital in Barcelona, Spain. Clinical charts were
                       ­reviewed to obtain clinical data. As a control group we used a random list of 225 patients diagnosed
                        in the hospital traumatology department in the same period, matched by age and sex.
                       Results: Diabetes was diagnosed in 40 GA patients (18%) (34 in the control group, 15%) and
                       ­hypothyroidism in 33 (15%) (22 in the control group 9.8%); the differences were not significant. We
                        also did not detect any association with uveitis, sarcoidosis, necrobiosis lipoidica, Sweet s­yndrome,
                        HIV infection, hepatitis B, or hematological malignancies. We only detected a possible ­association
                        with hepatitis C (6 GA patients, 2.7%, versus 0 controls, P = 0.03), and hypercholesterolemia
                        (108 GA patients, 48%, versus 79 controls, 35%, P = 0.007).
                       Conclusions: The possible pathogenic explanations for the association with hepatitis C and
                       ­hypercholesterolemia seem unlikely. We consider that the association of GA with other diseases,
                        ­including hypercholesterolemia and hepatitis C, is doubtful and that it there is no justification rule out
                         possible associated diseases in patients with GA.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022173                                                                              1
Introduction                                                       hematological neoplasms, sarcoidosis, Sweet syndrome, and
                                                                   association with drug treatments. The treatments carried out
Granuloma annulare (GA) is a disease of the skin and sub-          and the follow-up time of the patients were also recorded.
cutaneous tissue of unknown etiology characterized by an-
nular plaques, papules, or nodules containing foci of altered      Control Group
collagen surrounded by histiocytes and lymphocytes. It is a        For a control group, a random list of patients diagnosed in
relatively frequent entity with a benign clinical course that in   our hospital traumatology department between 2009 and
most cases does not require treatment [1,2]. It has been re-       2019, was used. For each case, a control of the same age
ported as associated with multiple diseases, mainly diabetes       and sex was randomly taken. For case and control, the clin-
mellitus (DM), thyroid diseases, and dyslipidemia. However,        ical history of the patients in the public health system was
the high frequency of some of these illnesses in the general       accessed to record whether they were diagnosed with the
population makes it difficult to assess whether the associa-       above cited entities by their primary care physician before
tion is real or fortuitous [1,3]. Although there are multiple      or during the year of the diagnosis of GA or of the visit to
studies on the subject, to date no adequately controlled stud-     traumatology. All controls were Caucasian except for 1 male
ies have been performed [1].                                       and 3 females of South American descent.


Objectives                                                         Statistical Analysis
                                                                   Data were explored with the SPSS 17.0 statistical package
Our objective was to review a series of patients with GA           for Windows. The proportions of cases with the possible as-
diagnosed histologically in the last 10 years in our hospital      sociated diseases in the group of patients with GA and in
in order to analyse their clinical features and the possible       the control group were compared using Fisher exact test.
association with other diseases.                                   The possible relationships between the different variables
                                                                   analyzed were also investigated. Categorical variables were
                                                                   compared using Fisher exact test. Continuous variables were
Methods
                                                                   compared using Student t test when the normality of the data
We carried out a retrospective observational study of a se-        distribution was confirmed. Otherwise, the Mann-Whitney
ries of 225 patients clinically and histologically diagnosed       U test was performed. Statistical significance was established
with GA between 2009 and 2019 at Bellvitge Hospital in             at a value of P < 0.05.
Barcelona. This is a tertiary referral university hospital
­
that provides healthcare to a population of approximately
                                                                   Results
1 ­million people. Cases registered as GA in the database of
the pathology department were reviewed. The diagnostic cri-        These were 225 patients, 155 women (69%) and 70 men
teria were the presence of palisaded granulomas with mucin         (31%), aged between 4 and 91 years (mean age 54.91 years,
deposition inside the granuloma.                                   standard deviation [SD] 16.296). At the time of diagnosis,
    Cases with lesions limited to the limbs or trunk were clas-    155 patients were older than 50 years (69%). All patients
sified as localized GA, while those with lesions on the trunk      with GA were Caucasian except for 2 women of South
and extremities (upper, lower, or both) were considered gen-       American descent. GA lesions involved the upper extremities
eralized GA [4]. Cases with epidermal perforation on biopsy        in 150 patients (hands 69, elbows 64, rest of the upper ex-
were diagnosed with perforating GA, and the cases with le-         tremities 78), the lower extremities in 92 (feet 15, knees 22,
sions limited to the hypodermis were classified as subcutane-      rest of the lower extremities 78), the trunk in 82 (­anterior
ous GA. Finally, cases with large erythematous or brownish         part of the trunk 70, posterior part 40), and the head and
smooth-surface macules on the trunk and extremities with-          neck region in 25 (19 neck, 6 face). Classic localized GA
out induration and with a histological pattern of interstitial     was the most frequent form of GA (124 cases, 55%) fol-
GA were classified as patch GA [5]. The medical records            lowed by generalized GA (72 cases, 32%), patch-type GA
of the patients were retrospectively reviewed to obtain the        (35 cases, 16%, some of them generalized), subcutaneous GA
following data: race, sex, age of the patients at the time of      (6 cases 2.7%) and perforating GA (4, 1.8%). Among the
diagnosis, date of diagnosis, evolution time of the lesions,       191 cases in which the extent of the lesions could be assessed,
number of lesions, location, clinical form of GA (localized,       117 had fewer than 10 lesions and 74 had more than 10
generalized, subcutaneous, perforating, and patch-type),           lesions. The time of evolution of the lesions at diagnosis was
duration of the lesions, presence of DM, hypercholesterol-         11.74 months, SD 19.284. The duration of the lesions until
emia, thyroid diseases, uveitis, HIV, hepatitis B, hepatitis C,    healing or the last follow-up was established in 112 cases,




2                                                                      Original Article | Dermatol Pract Concept. 2022;12(4):e2022173
ranging between 1 and 240 months (mean 31.46 months,               Conclusions
SD 39.921). In 68 of these 112 cases, the lesions persisted
for less than 2 years (61%). In 23 patients the lesions were       Although the incidence of GA in the population is unknown,
recurrent. The follow-up time of the patients ranged between       it is one of the most frequent chronic dermatological diseases.
1 and 120 months, with a mean follow-up of 21.83 months,           GA has been estimated to represent approximately 0.1–0.4%
SD 27.851. The prescribed treatments were: no treatment in         of dermatology outpatient visits in the United Kingdom [6]
46 patients, topical corticosteroids in 163, systemic cortico-     and 0.22-0.27% in the United States of ­America [7]. In our
steroids in 30, topical tacrolimus in 22, antimalarials in 14,     hospital we have not quantified the number of visits due to
intralesional corticosteroid infiltrations in 8, pentoxifylline    GA but the histological diagnosis of GA represents 0.97%
in 8, dapsone in 2, tetracyclines in 2, and isotretinoin in 1.     of the skin biopsies.
Twenty patients received 3 or more treatments.                        According to the literature, GA occurs more frequently
    Table 1 shows the clinical features of the lesions accord-     in the first 3 to 5 decades of life, with a ratio of women to
ing to the sex of the patients. Table 2 shows the diseases         men of around 1-2:1 [2]. In some series the percentage of
detected in the cases and in the controls.                         women is higher, up to 85% [7], being 69% in our series
    In the analysis of the possible relationships between the      (female / male ratio of 2.21 / 1). Regarding age, we had a
variables analyzed, the following relationships were signifi-      higher mean age than in other series (55 years, with 155
cant: male patients more frequently had hand lesions than          cases over 50 years), probably due to the lack of pediatrics
female patients (P = 0.017); female patients had lower limb        department in our hospital.
lesions more frequently than male patients (P = 0.002); pa-           It is known that GA lesions are usually located in the
tients with patch GA more frequently had lesions on the            extremities, especially the back of the hands and feet [2].
trunk (P = 0.020) and lower limbs (P = 0.013) than the rest        In our series, the upper extremities were affected in 150 pa-
of the patients; and finally, in a higher proportion of patients   tients (67%) and the lower extremities in 92 (41%), but the
with less than 10 lesions, the lesions involved the upper ex-      trunk was also frequently affected (82 cases, 36%). There are
tremities compared to the rest of the patients (P = 0.015).        five common clinical variants of GA (localized, generalized,
                                                                   patch-type, subcutaneous, and perforating). According to the



                           Table 1. Clinical features according to the sex of the patients.
                                                                   Female 155 (69%)          Male 70 (31%)
 Age, years                                                        54.62 SD 16.041           55.54 SD 16.948
 Evolution at diagnosis (months) 11.74 SD 19.284                   12.56 SD 21.874            9.87 SD 11.236
 Total duration (months) 31.36 SD 39.921                           32.92 SD 44.453           27.94 SD 26.330
 Upper limbs. N 150 (67%)                                           106/155 (68%)              44/70 (63%)          p = 0.017
   Hands 69                                                              40                        29               p = 0.006
   Elbows 64                                                             53                        11
   Rest 78                                                               60                        18
 Lower limbs, N 92 (41%)                                             75/155 (48%)              17/70 (24%)          p = 0.002
   Feet 15                                                                12                        3               p < 0.001
   Knees 22                                                               18                        4
   Rest 78                                                                67                       11
 Trunk, N 82 (36%)                                                   59/155 (38%)              23/70 (33%)
    Anterior 70                                                           49                       21
    Posterior 40                                                          29                       11
 Head and neck, N 25 (11%)                                            14/155 (9%)              11/70 (16%)
   Neck 19                                                                10                        9
   Face 6                                                                  4                        2
 Generalized, N 72 (32%)                                               54 (35%)                  18 (26%)
 Patch, N 35 (16%)                                                     26 (17%)                   9 (13%)
 Subcutaneous, N 6 (2.7%)                                               2 (1.3%)                 4 (5.7%)
 Perforating, N 4 (1.8%)                                                2 (1.3%)                 2 (2.9%)
 >10 lesions, N 74/191 (39%)                                         55/132 (42%)              19/59 (32%)
SD = standard deviation.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022173                                                                  3
                                 Table 2. Diseases detected in cases and in controls.
                                                        225 GA cases                    225 controls
 Age                                                  54.91 SD 16.296                 55.12 SD 16.321
 Sex (female/male), N                                      155/70                           155/70
 DM, N                                                    40 (18%)                        34 (15%)
 1                                                            3                               2
 2                                                           37                              32
 Hypothyroidism, N                                        33 (15%)                        22 (9.8%)
 Hypercholesterolemia, N                                 108 (48%)                        79 (35%)                    P = 0.007
 Hematologic neoplasms, N                                 4 (1.8%)                         1 (0.4%)
 HIV, N                                                   1 (0.4%)                             0
 Hepatitis B, N                                           3 (1.3%)                         1 (0.4%)
 Hepatitis C, N                                           6 (2.7%)                             0                      P = 0.030
 Sarcoidosis, N                                           1 (0.4%)                             0
 Necrobiosis lipoidica, N                                 1 (0.4%)                             0
 Uveitis, N                                                   0                                0
 Sweet syndrome, N                                            0                                0
DM = diabetes mellitus; SD = standard deviation.




literature, the most common is localized GA, accounting for         60 cases of generalized GA did not detect significant differ-
approximately 75% of GA cases. Generalized GA represents            ences with the control group (19% in the group with GA and
10-15% of cases [4,6] and is observed predominantly in              9.33% in the control group) [9]. For this reason, we consider
adults. It is defined as the presence of lesions on the trunk       it unlikely that GA is associated with malignant solid neo-
and extremities (upper or lower or both) [4]. Patch-type            plasms and we did not investigate this possibility it in the
GA is defined by the development of large erythematous or           present study.
brownish patches with a smooth surface on the trunk and                Diabetes mellitus (DM) is the disease most frequently
extremities with a histological pattern of interstitial GA [5].     analyzed as possibly being associated with GA. Some arti-
Perforating GA, characterized by umbilicated papules with a         cles suggest that there is a putative association [3,10-12],
central crust or a hyperkeratotic nucleus, and subcutaneous         especially with generalized GA [4], while other articles reject
GA are less frequent [1,2]. In our series we had a lower pro-       this [13-15]. The association with DM has been attributed
portion of localized GA (55%) and a higher proportion of            to microvascular dysfunction induced by diabetes. In addi-
generalized GA (32%) and patch-type GA (16%). This may              tion, as diabetes is associated with elevated inflammatory
be explained by the fact that our study only included his-          cytokines as well as T-cell and macrophage activation, it has
tologically confirmed cases diagnosed in a referral hospital        been suggested that diabetes may act as risk factor for GA
that receives the most doubtful, extensive, or persistent cases.    through dysregulated T-cell activity. In the present study, 40
This may also explain the high proportion of trunk lesions          of the 225 patients with GA (18%) were diabetic at diagno-
in our series.                                                      sis or had a diagnosis of DM in the subsequent 12 months,
    In previous studies, GA lesions resolved within 2 years in      compared to 34 in the control group (15%), a difference
50% of cases [8]. In our patients, the lesions resolved within      that was not statistically significant. Among the 72 cases of
2 years in 68 of 112 cases in which the duration of the le-         generalized GA, the incidence of DM was similar (13/72,
sions could be determined (61%). Although in our patients           18%) and the differences were therefore not significant ei-
GA lesions may have been extensive and persisted for long           ther. There are also several studies that suggest a possible
time, the only complication observed in them was secondary          association with thyroid diseases, especially hypothyroidism
elastolysis in some cases of generalized GA.                        [7,16]. As GA is considered an autoimmune disease, it has
    Various diseases have been considered as being possibly         been suggested that the association of GA with autoimmune
associated with GA, including metabolic, endocrinological,          thyroidal diseases may be based on a common immunoge-
autoimmune, granulomatous, infectious, and hematological            netic predisposition. In our study, 33 of our patients with
diseases. Although a possible association with malignant            GA (15%) were diagnosed with hypothyroidism compared
neoplasms has also been proposed based on isolated cases            to 22 in the control group (9.8%) and the difference was
and short series, a recent case-control study with a series of      also not significant. Other diseases that have been reported



4                                                                       Original Article | Dermatol Pract Concept. 2022;12(4):e2022173
with some frequency as being associated with GA are uveitis       in the general population and the lack of uniformity in the
[17,18], sarcoidosis [19,20], necrobiosis lipoidica [21], and     diagnostic criteria for hypercholesterolemia make these re-
Sweet syndrome [22]. In the present study we did not detect       sults difficult to assess. For this reason, despite the significant
a significant association with any of them. Regarding infec-      differences in the proportion of patients diagnosed with hy-
tions, possible associations with HIV infection, hepatitis B,     percholesterolemia among those with GA compared to the
and hepatitis C have been suggested [3]. We did not detect        control group in the present study, we consider a pathogenic
an association with HIV or hepatitis B, but 6 of our GA           relationship between both entities to be unlikely.
patients had positive serology for hepatitis C (2.7%) com-            One limitation of our study is that it is a retrospective
pared to none of the controls. Although the number of cases       survey and some clinical data of the patients are not included
is limited, the differences were significant (P = 0.03). As a     in the medical records. Another limitation is that these are
possible pathogenesis, it has been suggested that infection       cases diagnosed by biopsy in a referral hospital without pedi-
by hepatitis C virus may generate a cell-mediated immune          atrics department, so generalized cases may be overestimated
response that induces the formation of granulomas, since the      and the adult population may be overrepresented. As for the
presence of epithelioid granulomas in the liver has been de-      case-control study, the high frequency of some diseases in
tected in 10% of patients with HCV-related cirrhosis [23]. In     the general population makes it difficult to investigate a true
addition, in some patients with generalized GA and hepatitis      relationship with GA.
C, resolution of cutaneous lesions has been reported after            In summary, our study did not detect an association be-
hepatitis treatment [23,24]. Our data suggest that although       tween GA and pathologies such as DM and hypothyroid-
in some patients infection by hepatitis C virus may induce        ism. We only detected a significantly higher proportion of
GA, this situation is extremely rare, and in most cases GA is     patients with hypercholesterolemia and hepatitis C than in
not related to hepatitis C virus infection.                       the control group. However, the possible pathogenic expla-
    The most noteworthy of our results is that we detected a      nations for this association seem unlikely. We feel that asso-
significantly higher incidence of hypercholesterolemia among      ciation with other diseases, including hypercholesterolemia
patients with GA than among controls, 108 cases (48%) ver-        and hepatitis C, is doubtful and that it is not justified to
sus 79 cases (35%) (P = 0.007). The association of GA with        systematically rule out the existence of possible associated
dyslipidemia was detected in a previous study in which 80%        diseases in patients with GA.
of 140 patients with GA had dyslipidemia compared with
52% of the controls (P < 0.001) [25]. This survey also de-
tected a significant association with the extent of the lesions   References
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6                                                                             Original Article | Dermatol Pract Concept. 2022;12(4):e2022173
