Abstract
OBJECTIVES:
Herpes zoster has been widely described in the context of different systemic autoimmune diseases but not dermatomyositis/polymyositis. Therefore, we analyzed the prevalence, risk factors and herpes zoster outcomes in this population.
METHOD:
A retrospective cohort study of herpes zoster infections in dermatomyositis/polymyositis patients was performed. The patients were followed at a tertiary center from 1991 to 2012. For the control group, each patient with herpes zoster was paired with two patients without herpes zoster. Patients were matched by gender and the type of myositis, age at myositis onset and disease duration.
RESULTS:
Of 230 patients, 24 (10.4%) had a histories of herpes zoster (19 with dermatomyositis and five with polymyositis, two-thirds female). The mean age of the patients with herpes zoster was 44.6±16.8 years. No difference between the groups was found regarding cumulative clinical manifestations. Disease activity, autoantibody, muscle and leukogram parameters were also comparable between the groups. No differences in immunosuppressive (alone or in association with other immunosuppressive therapies) or glucocorticoid (current use, medium dose and cumulative dose in the last two months) therapies were found between patients with and without herpes zoster. However, a higher proportion of patients in the herpes zoster group received chloroquine diphosphate compared to the control group. All of the patients received acyclovir; 58.3% of patients had postherpetic neuralgia and no cases of recurrence were reported. Furthermore, individuals who were taking high prednisone doses at the time of the herpes zoster diagnosis had reduced levels of postherpetic neuralgia.
CONCLUSIONS:
These data suggest that chloroquine diphosphate could predispose patients with dermatomyositis/polymyositis to developing herpes zoster, particularly women and dermatomyositis patients.
Antimalarial; Chloroquine Diphosphate; Dermatomyositis; Herpes Zoster; Inflammatory Myopathies; Polymyositis; Risk Factors
INTRODUCTION
Idiopathic inflammatory myopathies encompass a heterogeneous group of systemic autoimmune diseases, including polymyositis (PM), which is characterized by symmetrical proximal and progressive muscle weakness of the limbs and dermatomyositis (DM), which, in addition to muscle involvement, includes skin abnormalities, such as heliotrope and Gottron's papules (11. Callen JP. Dermatomyositis. In: Callen JP (ed.). 2nd ed. Dermatological signs of internal disease. Philadelphia: W.B. Saunders; 1995.p.13-20.,22. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-7.).
Viral infections, such as herpes zoster (HZ), have been increasingly reported in individuals with
systemic autoimmune diseases. Among patients with systemic lupus erythematosus, for instance, there
is an HZ prevalence of 4.5% (33. Moga I, Formiga F, Canet R, Pac M, Mitjavila F, Pujol R. Herpes zoster vírus
infection in patients with systemic lupus erythematosus. Rev Clin Esp.
1995(8);195:530-3.) and an incidence of 6.4-58.7
events/1,000 patient-years (33. Moga I, Formiga F, Canet R, Pac M, Mitjavila F, Pujol R. Herpes zoster vírus
infection in patients with systemic lupus erythematosus. Rev Clin Esp.
1995(8);195:530-3.,44. Borba EF, Ribeiro AC, Martin P, Costa LP, Guedes LK, Bonfa E. Incidence, risk
factors, and outcome of herpes zoster in systemic lupus erythematosus. J Clin Rheumatol.
2010;16(3):119-22, http://dx.doi.org/10.1097/RHU.0b013e3181d52ed7.
http://dx.doi.org/10.1097/RHU.0b013e3181...
). Corticosteroids (33. Moga I, Formiga F, Canet R, Pac M, Mitjavila F, Pujol R. Herpes zoster vírus
infection in patients with systemic lupus erythematosus. Rev Clin Esp.
1995(8);195:530-3.) and immunosuppressive agents
(44. Borba EF, Ribeiro AC, Martin P, Costa LP, Guedes LK, Bonfa E. Incidence, risk
factors, and outcome of herpes zoster in systemic lupus erythematosus. J Clin Rheumatol.
2010;16(3):119-22, http://dx.doi.org/10.1097/RHU.0b013e3181d52ed7.
http://dx.doi.org/10.1097/RHU.0b013e3181...
5. Manzi S, Kuller LH, Kutzer J, Pazin GJ, Sinacore J, Medsger TA Jr, et al. Herpes
zoster in systemic lupus erythematosus. J Rheumatol. 1995;22 (7):1254-8.-66. Kahl LE. Herpes zoster infections in systemic lupus erythematosus: risk factors
and outcome. J Rheumatol. 1994;21(1):84-6.), disease
activity (55. Manzi S, Kuller LH, Kutzer J, Pazin GJ, Sinacore J, Medsger TA Jr, et al. Herpes
zoster in systemic lupus erythematosus. J Rheumatol. 1995;22 (7):1254-8.
6. Kahl LE. Herpes zoster infections in systemic lupus erythematosus: risk factors
and outcome. J Rheumatol. 1994;21(1):84-6.
7. Lee PP, Lee TL, Ho MH, Wong WH, Lau YL. Herpes zoster in juvenile-onset systemic
lupus erythematosus incidence, clinical characteristics and risk factors. Pediatr Infect Dis J.
2006;25(8):728-32, http://dx.doi.org/10.1097/01.inf.0000226841.03751.1f.
http://dx.doi.org/10.1097/01.inf.0000226...
-88. Kang TY, Lee HS, Kim TH, Jun JB, Yoo DH. Clinical and genetic risk factors of
herpes zoster in patients with systemic lupus erythematosus. Rheumatol Int. 2005;25(2):97-102,
http://dx.doi.org/10.1007/s00296-003-0403-3.
http://dx.doi.org/10.1007/s00296-003-040...
) and the
presence of anti-Sm autoantibodies (88. Kang TY, Lee HS, Kim TH, Jun JB, Yoo DH. Clinical and genetic risk factors of
herpes zoster in patients with systemic lupus erythematosus. Rheumatol Int. 2005;25(2):97-102,
http://dx.doi.org/10.1007/s00296-003-0403-3.
http://dx.doi.org/10.1007/s00296-003-040...
) number among the
possible risk factors for HZ in this population. The incidence of HZ in rheumatoid arthritis is 9.96
cases/1,000 patient-years (99. McDonald JR, Zeringue AL, Captan L, Ranganathan P, Xian H, Burroughs TE, et al.
Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect
Dis. 2009;48(10):1164-71.), and the risk factors in this
cohort include older age (>45 years old), the presence of cancer, chronic lung disease,
corticosteroid usage (1010. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk
of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom.
Arthritis Rheum. 2007;57(8):1431-8, http://dx.doi.org/10.1002/art.23112.
http://dx.doi.org/10.1002/art.23112...
), exposure to immunosuppressive
(1010. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk
of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom.
Arthritis Rheum. 2007;57(8):1431-8, http://dx.doi.org/10.1002/art.23112.
http://dx.doi.org/10.1002/art.23112...
) and immunobiological therapies (1111. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, et al.
Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents.
JAMA. 2009;301(7):737-44, http://dx.doi.org/10.1001/jama.2009.146.
http://dx.doi.org/10.1001/jama.2009.146...
) and immune system dysregulation (1212. Koetz K, Bryl E, Spickschen K, O'Fallon WM, Goronzy JJ, Weyand CM. T cell
homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(16):9203-8,
http://dx.doi.org/10.1073/pnas.97.16.9203.
http://dx.doi.org/10.1073/pnas.97.16.920...
).
Through a few epidemiological studies, HZ in DM/PM has been investigated within the context of
other opportunist infections or by examining a few myositis cases with HZ (1313. Fardet L, Rybojad M, Gain M, Kettaneh A, Cherin P, Bachelez H, et al. Incidence,
risk factors, and severity of herpes virus infections in a cohort of 121 patients with primary
dermatomyositis and dermatomyositis associated with a malignant neoplasm. Arch Dermatol
2009;145(8):889-93, http://dx.doi.org/10.1001/archdermatol.2009.152.
http://dx.doi.org/10.1001/archdermatol.2...
-(1515. Nagaoka S, Tani K, Ishigatsubo Y, Chiba J, Matsunaga K, Narita M, et al. Herpes
zoster in patients with dermatomyositis-polymyositis. Kansenshogaku Zasshi.
1990;64(11):1394-9.). Thus, Fardet et al. (1313. Fardet L, Rybojad M, Gain M, Kettaneh A, Cherin P, Bachelez H, et al. Incidence,
risk factors, and severity of herpes virus infections in a cohort of 121 patients with primary
dermatomyositis and dermatomyositis associated with a malignant neoplasm. Arch Dermatol
2009;145(8):889-93, http://dx.doi.org/10.1001/archdermatol.2009.152.
http://dx.doi.org/10.1001/archdermatol.2...
) analyzed the incidence, risk factors, and severity of HZ in 121
patients with DM. However, these authors evaluated HZ and herpes simplex in DM patients with and
without malignancy. Marie et al. (1414. Marie I, Ménard JF, Hachulla E, Chérin P, Benveniste O, Tiev K, et al.
Infectious complications in polymyositis and dermatomyositis: a series of 279 patients. Semin
Arthritis Rheum. 2011;41(1):48-60,
http://dx.doi.org/10.1016/j.semarthrit.2010.08.003.
http://dx.doi.org/10.1016/j.semarthrit.2...
) assessed several
opportunistic and severe infections in 279 patients with DM/PM for a period of 13 years, but they
found only three cases of HZ. Nagaoka et al. (1515. Nagaoka S, Tani K, Ishigatsubo Y, Chiba J, Matsunaga K, Narita M, et al. Herpes
zoster in patients with dermatomyositis-polymyositis. Kansenshogaku Zasshi.
1990;64(11):1394-9.) analyzed
the incidence of HZ in 22 patients with DM/PM over a period of 10 years. Five patients had histories
of this viral infection, which predominantly occurred in the remission stage of the disease, showing
no relationship with drug therapies.
Due to the dearth of publications on the topic, the aim of this study was to analyze the prevalence, risk factors and outcomes of HZ in our cohort of DM/PM patients.
MATERIALS AND METHODS
Study population, clinical assessment and data collection
Between January 1991 and January 2012, 230 consecutive patients with DM or PM and who fulfilled at least four of the five Bohan and Peter (22. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-7.) criteria were followed at a tertiary hospital. Twenty-four subjects (10.4%) in this group had histories of HZ. Of the remaining patients without HZ, a control group of 48 patients (two controls for every HZ patient) was formed and matched by gender, disease type (DM or PM), age at the onset of myositis and disease duration. The study was approved by the local Research Ethics Committee.
Demographics, drug therapy and clinical and laboratory data were retrospectively obtained through a systematic review of all patient medical records. Drug therapy and laboratory data were based on the time of the DM/PM diagnosis and the season in which the HZ event occurred, while the clinical manifestations considered were those presenting during the follow-up of these patients.
Constitutional symptoms, skin changes (e.g., heliotrope, Gottron's papules, ulcers, photosensitive, calcinosis, and vasculitis), joint involvement (arthralgia and/or arthritis), and gastrointestinal (dysphagia) and respiratory (dyspnea on moderate exertion) manifestations were analyzed.
Creatine kinase (normal range 24-173 IU/L) and aldolase (1.0-7.5 IU/L) were determined using an automated kinetic assay. Leukocyte count, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase were also assessed. The erythrocyte sedimentation rate and C-reactive protein levels were evaluated using the Westergren and nephelometry methods, respectively. Autoantibodies against cellular components were determined with indirect immunofluorescence using Hep-2 cells as the substrate. Autoantibody anti-Jo-1 was determined using the Western blotting method.
All of the patients were first started on corticosteroids (prednisone 1 mg/kg/day, administered orally), which were tapered gradually according to clinical and laboratory stability. In cases of high disease severity (dysphagia with risk of aspiration pneumonia, cutaneous vasculitis, or being refractory to oral corticosteroids), intravenous corticosteroids were administered (methyl prednisolone 1 g/day for three consecutive days). The following drugs were used alone or in combination for corticosteroid sparing: azathioprine (2-3 mg/kg/day), methotrexate (20-25 mg/week), cyclosporine (2-3 mg/kg/day), mycophenolate mofetil (2-3 g/day), leflunomide (20 mg/day), cyclophosphamide (0.5-1.0 g/m2 of body surface), intravenous human immunoglobulin (1 g/kg/day for two consecutive days) and chloroquine diphosphate (3-4 mg/kg/day).
Herpes zoster information
HZ infection was clinically defined by the appearance of the typical vesicular eruption
distributed in a dermatome. The potential complications of HZ, which were listed on the protocol
form, included postherpetic neuralgia (persistence of pain for more than one month after the
disappearance of the rash) (1616. Kost RG, Straus SE. Post herpetic neuralgia-pathogenesis, treatment, and
prevention. N Engl J Med. 1996;335(1):32-42.) and cutaneous dissemination
(vesicular lesions outside the primary and adjacent dermatomes) (1717. McCrary ML, Severson J, Tyring SK. Varicella zoster virus. J Am Acad Dermatol.
1999;41(1):1-14, http://dx.doi.org/10.1016/S0190-9622(99)70398-1.
http://dx.doi.org/10.1016/S0190-9622(99)...
). All of the lesions were initially evaluated by rheumatologists and then by
dermatologists from our service.
The disease status at the time of the HZ diagnosis was defined as (a) partial clinical response
(evidence of disease activity within the last 6 months of disease); (b) complete clinical response
(6-month continuous period with no evidence of disease activity while still receiving myositis
therapy); and (c) clinical remission (6-month continuous period with no evidence of disease activity
and no myositis therapy) (1717. McCrary ML, Severson J, Tyring SK. Varicella zoster virus. J Am Acad Dermatol.
1999;41(1):1-14, http://dx.doi.org/10.1016/S0190-9622(99)70398-1.
http://dx.doi.org/10.1016/S0190-9622(99)...
). Disease activity was defined
as an increase in muscle enzyme sera levels, with clinical evidence of limb muscle weakness at two
consecutive medical evaluations.
Statistical analysis
Continuous variables are expressed as the means±standard deviations (SDs), as medians with interquartile ranges (IQRs), or as percentages for categorical variables. Student's t-test or the Mann-Whitney U-test for continuous variables was employed to evaluate the differences between the DM/PM groups. The 95% confidence intervals (95% CI) were calculated using binomial distribution. All of the variables that significantly differed statistically in the univariable analysis (comparison between patients with and without HZ episodes or with and without neurological sequelae) were selected for adjustment. The sex- and age-adjusted odds ratios (ORs) and 95% CIs were calculated using an unconditional logistic model, and p<0.05 was considered statistically significant.
RESULTS
Demographic and clinical features of patients with and without herpes zoster
Over a 21-year follow-up period, 24 (10.4%) of 230 patients had HZ (19 DM cases and 5 PM cases, 3.8:1), and two-thirds were female. The clinical and demographic features of these patients are shown in Table 1). In general, these characteristics were comparable between the groups with and without HZ, except for a higher prevalence of DM in the group with HZ compared to the patients without HZ (p=0.046).
The mean age of the patients with HZ was 44.6±16.8 years (range 21 to 84 years). Demographic and clinical variables of the 24 patients in the HZ group were compared with those of the 48 randomly selected and matched patients without HZ, as shown in Table 2). No differences were detected between the two groups regarding the cumulative clinical manifestations (Table 2). Furthermore, the two groups were comparable in terms of current disease status, laboratory parameters (initial and current) and autoantibodies (Table 3).
All of the HZ patients initially received intravenous acyclovir (30 mg/kg/day).
There was no difference between DM/PM with and without HZ with regard to glucocorticoid therapy (current use, medium dose and cumulative dose over the two previous months). Similarly, immunosuppressive therapy use was similar in both groups (Table 4). However, the patients using chloroquine diphosphate had a 5.98-fold (95% CI, 1.66-22.26) greater risk of developing HZ compared to the patients who did not receive chloroquine diphosphate treatment.
Clinical evaluation and dermatome locations of herpes zoster
Table 5) shows the dermatome locations of HZ, as well as the clinical evaluations. Six cases had simultaneous involvement of two dermatomes. Neurological sequelae occurred in 14 (58.3%) of 24 patients, and no cases of HZ recurrence were reported. The duration of the neurological symptoms was 8.2±4.4 years.
The demographics, disease status and clinical and laboratory features were comparable in the patients with and without postherpetic neuralgia. However, the latter group used a higher prednisone dose at the time of the HZ diagnosis (median 40 mg/day [range 5-70]) than the former group (median 15 mg/day [range 0-40], p=0.018, with OR of 0.93 and 95% CI of 0.86-0.99).
DISCUSSION
The present study identified chloroquine diphosphate as the primary risk factor for HZ in DM/PM. In our population, we noted a high HZ prevalence that predominantly affected women and individuals with DM.
An important aspect of this retrospective study's design was its large cohort of HZ cases and associated risk factors in the patients with DM and PM, which are both considered rare systemic autoimmune diseases. Additionally, the study and control groups were matched by age because there is a known HZ cluster disparity between young and elderly subjects. Moreover, gender, disease type (DM or PM), age at diagnosis and disease duration were also controlled for by sample matching to avoid a confounding bias.
Despite enrolling large samples, many authors have found few HZ cases in their DM/PM populations.
Notably, Marie et al. (1414. Marie I, Ménard JF, Hachulla E, Chérin P, Benveniste O, Tiev K, et al.
Infectious complications in polymyositis and dermatomyositis: a series of 279 patients. Semin
Arthritis Rheum. 2011;41(1):48-60,
http://dx.doi.org/10.1016/j.semarthrit.2010.08.003.
http://dx.doi.org/10.1016/j.semarthrit.2...
) identified only three individuals
with HZ in 279 cases and Yu et al. (1818. Yu KH, Wu YJ, Kuo CF, See LC, Shen YM, Chang HC, et al. Survival analysis of
patients with dermatomyositis and polymyositis: analysis of 192 Chinese cases. Clin Rheumatol.
2011;30(12):1595-601, http://dx.doi.org/10.1007/s10067-011-1840-0.
http://dx.doi.org/10.1007/s10067-011-184...
) detected two subjects
with HZ among 192 cases of DM/PM, whereas Fardet et al. (1313. Fardet L, Rybojad M, Gain M, Kettaneh A, Cherin P, Bachelez H, et al. Incidence,
risk factors, and severity of herpes virus infections in a cohort of 121 patients with primary
dermatomyositis and dermatomyositis associated with a malignant neoplasm. Arch Dermatol
2009;145(8):889-93, http://dx.doi.org/10.1001/archdermatol.2009.152.
http://dx.doi.org/10.1001/archdermatol.2...
)
found 16 HZ cases among 121 DM patients. In the present study, we evaluated 24 (10.4%) HZ cases
among 230 patients who were clinically diagnosed with DM/PM over a 21-year follow-up period.
Therefore, a considerable number of infected patients were identified in this population.
Based on other systemic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid
arthritis, the major risk factors for developing HZ include older age, use of corticosteroids and
immunosuppressive agents, disease activity, female sex, cancer, lung disease and impaired cellular
immunity (33. Moga I, Formiga F, Canet R, Pac M, Mitjavila F, Pujol R. Herpes zoster vírus
infection in patients with systemic lupus erythematosus. Rev Clin Esp.
1995(8);195:530-3.
4. Borba EF, Ribeiro AC, Martin P, Costa LP, Guedes LK, Bonfa E. Incidence, risk
factors, and outcome of herpes zoster in systemic lupus erythematosus. J Clin Rheumatol.
2010;16(3):119-22, http://dx.doi.org/10.1097/RHU.0b013e3181d52ed7.
http://dx.doi.org/10.1097/RHU.0b013e3181...
5. Manzi S, Kuller LH, Kutzer J, Pazin GJ, Sinacore J, Medsger TA Jr, et al. Herpes
zoster in systemic lupus erythematosus. J Rheumatol. 1995;22 (7):1254-8.
6. Kahl LE. Herpes zoster infections in systemic lupus erythematosus: risk factors
and outcome. J Rheumatol. 1994;21(1):84-6.
7. Lee PP, Lee TL, Ho MH, Wong WH, Lau YL. Herpes zoster in juvenile-onset systemic
lupus erythematosus incidence, clinical characteristics and risk factors. Pediatr Infect Dis J.
2006;25(8):728-32, http://dx.doi.org/10.1097/01.inf.0000226841.03751.1f.
http://dx.doi.org/10.1097/01.inf.0000226...
8. Kang TY, Lee HS, Kim TH, Jun JB, Yoo DH. Clinical and genetic risk factors of
herpes zoster in patients with systemic lupus erythematosus. Rheumatol Int. 2005;25(2):97-102,
http://dx.doi.org/10.1007/s00296-003-0403-3.
http://dx.doi.org/10.1007/s00296-003-040...
9. McDonald JR, Zeringue AL, Captan L, Ranganathan P, Xian H, Burroughs TE, et al.
Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect
Dis. 2009;48(10):1164-71.
10. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk
of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom.
Arthritis Rheum. 2007;57(8):1431-8, http://dx.doi.org/10.1002/art.23112.
http://dx.doi.org/10.1002/art.23112...
11. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, et al.
Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents.
JAMA. 2009;301(7):737-44, http://dx.doi.org/10.1001/jama.2009.146.
http://dx.doi.org/10.1001/jama.2009.146...
-1212. Koetz K, Bryl E, Spickschen K, O'Fallon WM, Goronzy JJ, Weyand CM. T cell
homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(16):9203-8,
http://dx.doi.org/10.1073/pnas.97.16.9203.
http://dx.doi.org/10.1073/pnas.97.16.920...
,1919. Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med.
2005;352(22):2266-7.
20. Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes
zoster? Lancet Infect Dis. 2004;4(1):26-33,
http://dx.doi.org/10.1016/S1473-3099(03)00857-0.
http://dx.doi.org/10.1016/S1473-3099(03)...
-2121. Wolfe F, Michaud K, Chakravarty EF. Rates and predictors of herpes zoster in
patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. Rheumatology.
2006;45(11):1370-5, http://dx.doi.org/10.1093/rheumatology/kel328.
http://dx.doi.org/10.1093/rheumatology/k...
).
In our population, HZ predominantly affected adults with a mean age of 44 years (range 21 to 84 years), with no tendency toward affecting older individuals. Moreover, to avoid analysis bias, individuals with neoplasias were excluded.
In contrast with other systemic autoimmune diseases, in which impaired cellular immunity is
considered a risk factor for HZ development (1212. Koetz K, Bryl E, Spickschen K, O'Fallon WM, Goronzy JJ, Weyand CM. T cell
homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(16):9203-8,
http://dx.doi.org/10.1073/pnas.97.16.9203.
http://dx.doi.org/10.1073/pnas.97.16.920...
), humoral
immunity function might be considered relevant in inflammatory myopathies because the prevalence of
HZ was higher in the DM patients compared to the PM patients. From an immunopathological standpoint,
CD8 (+) lymphocyte and macrophage infiltrations are primarily found in PM muscle fibers (2222. Botet JC, Grau JM, Casademont J, Urbano-Marquez A, Rozman C. Characterization of
mononuclear exudates in idiopathic inflammatory myopathies. Virchows Arch A Pathol Anat Histopathol.
1988;412(4):371-4, http://dx.doi.org/10.1007/BF00750264.
http://dx.doi.org/10.1007/BF00750264...
), whereas in DM, B cells play important roles in the
pathogenesis of the disease through the presence of autoantibodies, immune complex deposition in the
dermoepidermal junction of skin lesions and the presence of B cells in inflamed muscles and
perivascular areas (2323. Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced
dermatomyositis: a quantitative study. Ann Neurol. 1990;27(4):343-56,
http://dx.doi.org/10.1002/ana.410270402.
http://dx.doi.org/10.1002/ana.410270402...
,2424. Engel AG, Arahata K. Mononuclear cells in myopathies: quantitation of
functionally distinct subsets, recognition of antigen specific cell-mediated cytotoxicity in some
diseases, and implications for the pathogenesis of the different inflammatory myopathies. Hum
Pathol. 1986;17(7):704-21, http://dx.doi.org/10.1016/S0046-8177(86)80180-0.
http://dx.doi.org/10.1016/S0046-8177(86)...
). Additionally, deposition of complement and immunoglobulin in the perifascicular
endothelium can lead to ischemia and muscle atrophy, underlining the importance of humoral immunity
(2525. Noss EH, Hausner-Sypek DL, Weinblatt M. Rituximab as therapy for refractory
polymyositis and dermatomyositis. J Rheumatol. 2006;33(5):1021-6.). Thus, disturbances in humoral immunity might increase
HZ reactivation, as we found a higher prevalence of HZ in the DM patients compared to the PM
patients.
Nagaoka et al. (1515. Nagaoka S, Tani K, Ishigatsubo Y, Chiba J, Matsunaga K, Narita M, et al. Herpes zoster in patients with dermatomyositis-polymyositis. Kansenshogaku Zasshi. 1990;64(11):1394-9.) analyzed five HZ cases among 22 DM/PM patients and noted that the infection affected more patients without disease activity; they found no correlation over time with corticosteroid use. Our results showed that HZ prevalence was independent of disease status and clinical and laboratory features, including cutaneous manifestations. Moreover, daily and/or cumulative dosages of corticosteroid and/or intravenous pulse methylprednisolone did not increase the risk for HZ development in our population. Likewise, using immunosuppressive therapy (methotrexate, azathioprine, mycophenolate mofetil, leflunomide and cyclophosphamide)—either alone or in combination—was not associated with HZ.
However, patients using chloroquine diphosphate had a fivefold greater risk of developing HZ
compared to patients not receiving chloroquine diphosphate treatment. Chloroquine diphosphate and
its analogue, hydroxychloroquine, are used to treat various rheumatic diseases, such as rheumatoid
arthritis, systemic lupus erythematosus, sarcoidosis, dermatomyositis, Sjögren's syndrome, chronic
juvenile arthritis and psoriatic arthritis; these drugs offer clinical benefits with acceptable
safety profiles (2626. Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjögren's syndrome
with hydroxychloroquine: a retrospective, open-label study. Lupus. 1996;5 Suppl 1:S31-6,
http://dx.doi.org/10.1177/096120339600500108.
http://dx.doi.org/10.1177/09612033960050...
27. Meinao IM, Sato EI, Andrade LEC, Ferraz MB, Atra E. Controlled trial with
chloroquine diphosphate in systemic lupus erythematosus. Lupus. 1996;5(3):237-41,
http://dx.doi.org/10.1177/096120339600500313.
http://dx.doi.org/10.1177/09612033960050...
28. Olson NY, Lindsley CB. Adjunctive use of hydroxychloroquine in childhood
dermatomyositis. J Rheumatol. 1986;16(12):1545-7.-2929. Ryes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J
Rheumatol. 1997;36(7):799-805.). Further, these drugs have also been used to treat inflammatory myopathies, particularly
for the cutaneous symptoms of DM (3030. Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno R, Hawkins C. Cutaneous
lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol.
1984;10(4):592-600, http://dx.doi.org/10.1016/S0190-9622(84)80263-7.
http://dx.doi.org/10.1016/S0190-9622(84)...
31. Ang GC, Werth VP. Combination antimalarials in the treatment of cutaneous
dermatomyositis. A Retrospective Study. Arch Dermatol. 2005;141(7):855-9,
http://dx.doi.org/10.1001/archderm.141.7.855.
http://dx.doi.org/10.1001/archderm.141.7...
32. Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more
common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch
Dermatol. 2002;138(9):1231-3, http://dx.doi.org/10.1001/archderm.138.9.1231.
http://dx.doi.org/10.1001/archderm.138.9...
33. Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno R, Hawkins C. Cutaneous
lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol.
1984;10(4):592-600, http://dx.doi.org/10.1016/S0190-9622(84)80263-7.
http://dx.doi.org/10.1016/S0190-9622(84)...
-3434. Sato JO, Sallum AM, Ferriani VP, Marini R, Sacchetti SB, Okuda EM, et al.
Rheumatology Committee of the São Paulo Paediatrics Society. A Brazilian registry of juvenile
dermatomyositis: onset features and classification of 189 cases. Clin Exp Rheumatol.
2009;27(6):1031-8.).
Chloroquine might also have antiviral activity (3535. Savirno A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on
viral infections: an old drug against today's diseases? Lancet Infect Dis.
2003;3(11):772-7.). As a
lysosomotropic weak base, it impairs the replication of some viruses by reducing the efficiency of
endosome-mediated virus entry or by inhibiting low-pH-dependent proteases in trans-Golgi vesicles
(3535. Savirno A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on
viral infections: an old drug against today's diseases? Lancet Infect Dis.
2003;3(11):772-7.). Its antiviral activity against the human
immunodeficiency virus (3636. Boelaert JR, Piette J, Sperber K. The potential place of chloroquine in the
treatment of HIV-1-infected patients. J Clin Virol. 2001;20(3):137-40,
http://dx.doi.org/10.1016/S1386-6532(00)00140-2.
http://dx.doi.org/10.1016/S1386-6532(00)...
) and the SARS coronavirus has also
been demonstrated (3737. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of
severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Comm.
2004;323(1):264-8, http://dx.doi.org/10.1016/j.bbrc.2004.08.085.
http://dx.doi.org/10.1016/j.bbrc.2004.08...
,3838. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah,
et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J.
2005,2:69, http://dx.doi.org/10.1186/1743-422X-2-69.
http://dx.doi.org/10.1186/1743-422X-2-69...
). However, chloroquine has also been shown to increase symptom severity and mortality
(e.g., following Semliki Forest virus and encephalomyocarditis virus infection, as well as
increasing viral titers in various organs) (3939. Sidhu GS, Gaddipati JP, Vogel SN, Maheshwari RK. Acceleraton of viral
replication and up-regulation of cytokine levels by antimalarials: implications in malaria-endemic
areas. Am J Trop Med Hyg. 1999;61(2):180-6.). Our results
clearly showed that chloroquine was a risk factor for HZ development in subjects with DM/PM,
independent of disease status, therapy and demographic features.
Regarding the clinical evaluation, at least half of our patients had neurological sequelae. Six
patients had simultaneous involvement of two dermatomes, while no cases of HZ recurrence were
reported. Postherpetic neuralgia can result in severe pain such that patients are often unable to
wear clothing that comes in contact with the lesions or be exposed to wind because of high skin
sensitivity in regions such as the thorax and face. The incidence of postherpetic neuralgia rises
from 10% among individuals of all ages to as high as 40% among those aged 50 years and older (4040. Dworkin RH, Schmader KE. The epidemiology and natural history of herpes zoster
and postherpetic neuralgia. In: Watson CPN, editor. Herpes zoster and post - herpetic neuralgia.
Amsterdam (Netherlands): Elsevier; 2001.p.39-64.). A large prospective study identified four independent
predictors of postherpetic neuralgia: older age, severe, acute pain, severe rash and a shorter
duration of rash before consultation (4141. Opstelten W, Zuithoff NPA, van Essen GA, van Loon AM, van Wijck AJ, Kalkman CJ,
et al. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster:
prospective prognostic study. Pain. 2007;132;Suppl 1:S52-9,
http://dx.doi.org/10.1016/j.pain.2007.02.004.
http://dx.doi.org/10.1016/j.pain.2007.02...
). Although
controversial, short-term use of corticosteroids can reduce the pain severity and improve patient
quality of life in the acute phase (4242. Ernst ME, Santee JA, Klepser TB. Oral corticosteroids for pain associated with
herpes zoster. Ann Pharmacother 1998;32(10):1099-103,
http://dx.doi.org/10.1345/aph.18041.
http://dx.doi.org/10.1345/aph.18041...
). Note that high
prednisone doses at the time of HZ diagnosis were found to decrease the incidence of postherpetic
neuralgia in our patients.
In conclusion, our data showed a high prevalence of HZ in the DM/PM population studied and confirmed that chloroquine diphosphate is a risk factor for HZ development in this population, particularly women and DM patients. Further research is necessary to evaluate the possible molecular mechanism underlying the higher HZ prevalence in DM subjects compared to PM patient populations.
This study was partially supported by the Federico Foundation.
REFERENCES
-
1Callen JP. Dermatomyositis. In: Callen JP (ed.). 2nd ed. Dermatological signs of internal disease. Philadelphia: W.B. Saunders; 1995.p.13-20.
-
2Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-7.
-
3Moga I, Formiga F, Canet R, Pac M, Mitjavila F, Pujol R. Herpes zoster vírus infection in patients with systemic lupus erythematosus. Rev Clin Esp. 1995(8);195:530-3.
-
4Borba EF, Ribeiro AC, Martin P, Costa LP, Guedes LK, Bonfa E. Incidence, risk factors, and outcome of herpes zoster in systemic lupus erythematosus. J Clin Rheumatol. 2010;16(3):119-22, http://dx.doi.org/10.1097/RHU.0b013e3181d52ed7.
» http://dx.doi.org/10.1097/RHU.0b013e3181d52ed7 -
5Manzi S, Kuller LH, Kutzer J, Pazin GJ, Sinacore J, Medsger TA Jr, et al. Herpes zoster in systemic lupus erythematosus. J Rheumatol. 1995;22 (7):1254-8.
-
6Kahl LE. Herpes zoster infections in systemic lupus erythematosus: risk factors and outcome. J Rheumatol. 1994;21(1):84-6.
-
7Lee PP, Lee TL, Ho MH, Wong WH, Lau YL. Herpes zoster in juvenile-onset systemic lupus erythematosus incidence, clinical characteristics and risk factors. Pediatr Infect Dis J. 2006;25(8):728-32, http://dx.doi.org/10.1097/01.inf.0000226841.03751.1f.
» http://dx.doi.org/10.1097/01.inf.0000226841.03751.1f -
8Kang TY, Lee HS, Kim TH, Jun JB, Yoo DH. Clinical and genetic risk factors of herpes zoster in patients with systemic lupus erythematosus. Rheumatol Int. 2005;25(2):97-102, http://dx.doi.org/10.1007/s00296-003-0403-3.
» http://dx.doi.org/10.1007/s00296-003-0403-3 -
9McDonald JR, Zeringue AL, Captan L, Ranganathan P, Xian H, Burroughs TE, et al. Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect Dis. 2009;48(10):1164-71.
-
10Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007;57(8):1431-8, http://dx.doi.org/10.1002/art.23112.
» http://dx.doi.org/10.1002/art.23112 -
11Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301(7):737-44, http://dx.doi.org/10.1001/jama.2009.146.
» http://dx.doi.org/10.1001/jama.2009.146 -
12Koetz K, Bryl E, Spickschen K, O'Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(16):9203-8, http://dx.doi.org/10.1073/pnas.97.16.9203.
» http://dx.doi.org/10.1073/pnas.97.16.9203 -
13Fardet L, Rybojad M, Gain M, Kettaneh A, Cherin P, Bachelez H, et al. Incidence, risk factors, and severity of herpes virus infections in a cohort of 121 patients with primary dermatomyositis and dermatomyositis associated with a malignant neoplasm. Arch Dermatol 2009;145(8):889-93, http://dx.doi.org/10.1001/archdermatol.2009.152.
» http://dx.doi.org/10.1001/archdermatol.2009.152 -
14Marie I, Ménard JF, Hachulla E, Chérin P, Benveniste O, Tiev K, et al. Infectious complications in polymyositis and dermatomyositis: a series of 279 patients. Semin Arthritis Rheum. 2011;41(1):48-60, http://dx.doi.org/10.1016/j.semarthrit.2010.08.003.
» http://dx.doi.org/10.1016/j.semarthrit.2010.08.003 -
15Nagaoka S, Tani K, Ishigatsubo Y, Chiba J, Matsunaga K, Narita M, et al. Herpes zoster in patients with dermatomyositis-polymyositis. Kansenshogaku Zasshi. 1990;64(11):1394-9.
-
16Kost RG, Straus SE. Post herpetic neuralgia-pathogenesis, treatment, and prevention. N Engl J Med. 1996;335(1):32-42.
-
17McCrary ML, Severson J, Tyring SK. Varicella zoster virus. J Am Acad Dermatol. 1999;41(1):1-14, http://dx.doi.org/10.1016/S0190-9622(99)70398-1.
» http://dx.doi.org/10.1016/S0190-9622(99)70398-1 -
18Yu KH, Wu YJ, Kuo CF, See LC, Shen YM, Chang HC, et al. Survival analysis of patients with dermatomyositis and polymyositis: analysis of 192 Chinese cases. Clin Rheumatol. 2011;30(12):1595-601, http://dx.doi.org/10.1007/s10067-011-1840-0.
» http://dx.doi.org/10.1007/s10067-011-1840-0 -
19Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med. 2005;352(22):2266-7.
-
20Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis. 2004;4(1):26-33, http://dx.doi.org/10.1016/S1473-3099(03)00857-0.
» http://dx.doi.org/10.1016/S1473-3099(03)00857-0 -
21Wolfe F, Michaud K, Chakravarty EF. Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. Rheumatology. 2006;45(11):1370-5, http://dx.doi.org/10.1093/rheumatology/kel328.
» http://dx.doi.org/10.1093/rheumatology/kel328 -
22Botet JC, Grau JM, Casademont J, Urbano-Marquez A, Rozman C. Characterization of mononuclear exudates in idiopathic inflammatory myopathies. Virchows Arch A Pathol Anat Histopathol. 1988;412(4):371-4, http://dx.doi.org/10.1007/BF00750264.
» http://dx.doi.org/10.1007/BF00750264 -
23Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol. 1990;27(4):343-56, http://dx.doi.org/10.1002/ana.410270402.
» http://dx.doi.org/10.1002/ana.410270402 -
24Engel AG, Arahata K. Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies. Hum Pathol. 1986;17(7):704-21, http://dx.doi.org/10.1016/S0046-8177(86)80180-0.
» http://dx.doi.org/10.1016/S0046-8177(86)80180-0 -
25Noss EH, Hausner-Sypek DL, Weinblatt M. Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol. 2006;33(5):1021-6.
-
26Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjögren's syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus. 1996;5 Suppl 1:S31-6, http://dx.doi.org/10.1177/096120339600500108.
» http://dx.doi.org/10.1177/096120339600500108 -
27Meinao IM, Sato EI, Andrade LEC, Ferraz MB, Atra E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus. 1996;5(3):237-41, http://dx.doi.org/10.1177/096120339600500313.
» http://dx.doi.org/10.1177/096120339600500313 -
28Olson NY, Lindsley CB. Adjunctive use of hydroxychloroquine in childhood dermatomyositis. J Rheumatol. 1986;16(12):1545-7.
-
29Ryes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol. 1997;36(7):799-805.
-
30Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno R, Hawkins C. Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol. 1984;10(4):592-600, http://dx.doi.org/10.1016/S0190-9622(84)80263-7.
» http://dx.doi.org/10.1016/S0190-9622(84)80263-7 -
31Ang GC, Werth VP. Combination antimalarials in the treatment of cutaneous dermatomyositis. A Retrospective Study. Arch Dermatol. 2005;141(7):855-9, http://dx.doi.org/10.1001/archderm.141.7.855.
» http://dx.doi.org/10.1001/archderm.141.7.855 -
32Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch Dermatol. 2002;138(9):1231-3, http://dx.doi.org/10.1001/archderm.138.9.1231.
» http://dx.doi.org/10.1001/archderm.138.9.1231 -
33Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno R, Hawkins C. Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol. 1984;10(4):592-600, http://dx.doi.org/10.1016/S0190-9622(84)80263-7.
» http://dx.doi.org/10.1016/S0190-9622(84)80263-7 -
34Sato JO, Sallum AM, Ferriani VP, Marini R, Sacchetti SB, Okuda EM, et al. Rheumatology Committee of the São Paulo Paediatrics Society. A Brazilian registry of juvenile dermatomyositis: onset features and classification of 189 cases. Clin Exp Rheumatol. 2009;27(6):1031-8.
-
35Savirno A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):772-7.
-
36Boelaert JR, Piette J, Sperber K. The potential place of chloroquine in the treatment of HIV-1-infected patients. J Clin Virol. 2001;20(3):137-40, http://dx.doi.org/10.1016/S1386-6532(00)00140-2.
» http://dx.doi.org/10.1016/S1386-6532(00)00140-2 -
37Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Comm. 2004;323(1):264-8, http://dx.doi.org/10.1016/j.bbrc.2004.08.085.
» http://dx.doi.org/10.1016/j.bbrc.2004.08.085 -
38Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005,2:69, http://dx.doi.org/10.1186/1743-422X-2-69.
» http://dx.doi.org/10.1186/1743-422X-2-69 -
39Sidhu GS, Gaddipati JP, Vogel SN, Maheshwari RK. Acceleraton of viral replication and up-regulation of cytokine levels by antimalarials: implications in malaria-endemic areas. Am J Trop Med Hyg. 1999;61(2):180-6.
-
40Dworkin RH, Schmader KE. The epidemiology and natural history of herpes zoster and postherpetic neuralgia. In: Watson CPN, editor. Herpes zoster and post - herpetic neuralgia. Amsterdam (Netherlands): Elsevier; 2001.p.39-64.
-
41Opstelten W, Zuithoff NPA, van Essen GA, van Loon AM, van Wijck AJ, Kalkman CJ, et al. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study. Pain. 2007;132;Suppl 1:S52-9, http://dx.doi.org/10.1016/j.pain.2007.02.004.
» http://dx.doi.org/10.1016/j.pain.2007.02.004 -
42Ernst ME, Santee JA, Klepser TB. Oral corticosteroids for pain associated with herpes zoster. Ann Pharmacother 1998;32(10):1099-103, http://dx.doi.org/10.1345/aph.18041.
» http://dx.doi.org/10.1345/aph.18041
-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
May 2013
History
-
Received
10 Dec 2012 -
Reviewed
1 Jan 2013 -
Accepted
12 Jan 2013