Abstract
Statins are commonly prescribed to reduce cardiovascular risk, but statin-induced myopathy is a leading cause for therapy discontinuation. This case report discusses a 69-year-old female with multiple comorbidities, including smoldering multiple myeloma, who presented with myalgias and a vesicular rash initially suspected to be herpes zoster due to her immunocompromised status. Elevated creatine kinase (CK) levels were noted (>9000 U/L) while the patient was on high-dose atorvastatin. Despite initial suspicions of herpes zoster, the rash’s atypical progression led to further evaluation, revealing a more complex picture. The patient had a significant history of drug allergies, complicating the diagnosis, particularly following recent clindamycin treatment for a dental issue. After discontinuing atorvastatin and clindamycin, her CK levels improved, and subsequent testing confirmed the presence of anti-HMG-CoA reductase antibodies, establishing a diagnosis of statin-induced autoimmune necrotizing myopathy. This case underscores the importance of detailed patient histories and the need to consider drug-induced hypersensitivity reactions in immunocompromised individuals. The resolution of symptoms after stopping the offending medications emphasizes the critical role of careful monitoring and diagnosis in managing patients with complex medical backgrounds.
Keywords: Statin-induced myopathy, Drug allery, Herpes zoster, Immunocompromised
Introduction
HMG-CoA reductase inhibitors (statins) are the most commonly prescribed medications to reduce cardiovascular risk in certain individuals. However, the leading cause of discontinuing statin therapy is statin-induced myopathy. In most cases, muscle symptoms related to statins are self-limiting, but they can also result from autoimmune necrotizing myopathy, characterized by positive anti-HMG-CoA reductase antibodies, progressive muscle weakness, elevated CK levels, and muscle necrosis on biopsy [1].
Varicella Zoster virus belongs to the family of human alpha-herpesvirus, which causes chickenpox in children as the primary infection in the non-vaccinated pre-dominant areas. It first appears as skin eruption with lesions starting as crops, transitioning from papules to vesicles to crust, and eventually disappearing. After the initial infection resolves, the virus becomes dormant in peripheral autonomic ganglions, including the dorsal and trigeminal ganglions. Decades later, the virus can be reactivated spontaneously in the setting of an immunocompromised state causing herpes zoster rash that appears as vesicular, pruritic painful eruption along dermatomal distribution [2].
Drug-induced hypersensitivity can present as an immediate type 1 IgE-mediated reaction, occurring acutely within minutes to hours of drug exposure. This may manifest as a maculopapular rash, urticaria, angioedema, bronchospasm, or anaphylaxis. Alternatively, it can present as a delayed-type T-cell-mediated hypersensitivity reaction, developing over several days to weeks. It may appear as maculopapular exanthem, contact dermatitis, nephritis, hepatitis, or fixed drug eruptions [3].
Our patient presented with myalgias and a painful vesicular rash, initially suspected to be herpes zoster due to his immunocompromised status. However, it was later diagnosed as statin-induced autoimmune necrotizing myopathy and a drug-induced delayed hypersensitivity reaction.
Case presentation
69-year-old female with a past medical history of HTN, HLD, GERD, smoldering multiple myeloma without CRAB, non-obstructive CAD, myopericarditis, pericardial effusion, non-ischemic cardiomyopathy presented with a painful erythematous rash with non-blanching papules on trunk, torso, neck, and face sparing extremities, as shown in Fig. 1 below.
Fig. 1.
Erythematous rash with nonblanching papules on trunk, torso, neck and face sparing extremities.
The Patient was lost to follow up with Oncology for her MM, so the provisional diagnosis of diffuse herpes zoster was considered in the assumption of her compromised immunity, painful rash and clinical findings of microvesicles on her neck. The patient's initial CK levels were reported to be > 9000. The Patient was on high-dose atorvastatin and colchicine for nonischemic cardiomyopathy and myopericarditis, respectively. Both agents are culprits for myopathy.
Labs ordered during her stay in the hospital are given in Table 1 below.Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10
Table 1.
Serial CPK levels.
| Component Latest Ref Rng |
6/20/2024 | 6/22/2024 | 6/23/2024 | 6/24/2024 | 6/25/2024 | 6/27/2024 | 6/28/2024 |
|---|---|---|---|---|---|---|---|
| CPK 20–170 U/L |
9901 (H) | 5481 (H) | 4944 (H) | 4329 (H) | 3833 (H) | 3573 (H) | 4105 (H) |
Table 2.
Serial WBC count and CRP levels of the patient.
| Component Latest Ref Rng |
6/23/2024 | 6/24/2024 | 6/25/2024 | 6/26/2024 | 6/27/2024 | 6/28/2024 |
|---|---|---|---|---|---|---|
| WBC 4.80–10.80 × 10(3)/mcL |
19.74 (H) | 18.83 (H) | 16.30 (H) | 12.11 (H) | 8.91 | 6.65 |
| High Sensitive C-Reactive Protein < =5.00 mg/L |
101.00 (H) | 111.50 (H) | 139.20 (H) | 60.70 (H) |
Table 3.
Antistreptolysin O levels and HIV AG/Ab reactivity.
| Component Latest Ref Rng |
6/24/2024 | Component Latest Ref Rng |
6/24/2024 |
|---|---|---|---|
| Anti-streptolysin O 0–199 IU/mL |
21 | HIV 1,2 AG/Ab by CMIA Non Reactive |
Non Reactive |
Table 4.
HCV panel and aldolase levels of the patient.
| Component Latest Ref Rng |
6/21/2024 | Component Latest Ref Rng |
6/21/2024 |
|---|---|---|---|
| Hepatitis C Ab S/CO |
N/A | Aldolase 3.3–10.3 U/L |
51.9 (H) |
| HCV S/CO Ratio 0.00–0.99 S/CO |
0.07 | ||
| HCV Interpretation Nonreactive |
Nonreactive |
Table 5.
ANA and Treponema Pallidum Ab Screen of the patient.
| Component Latest Ref Rng |
6/21/2024 | Component Latest Ref Rng |
6/21/2024 |
|---|---|---|---|
| Antinuclear Ab (ANA) < 1:80 |
Negative | Treponema Pallidum Ab Screen I Negative |
Negative |
Table 6.
ANCA and Antismooth muscle Ab levels of the patient.
| Component Latest Ref Rng |
6/21/2024 | Component Latest Ref Rng |
6/21/2024 |
|---|---|---|---|
| Cytoplasmic (C-ANCA) AB Negative |
Negative | Antismooth Muscle Ab, IFA < 1:20 |
< 1:20 |
| Perinuclear (P-ANCA) AB Negative |
Negative |
Table 7.
SS-A, SS-B, and VZV IgM levels.
| Component Latest Ref Rng |
6/21/2024 | Component Latest Ref Rng |
6/21/2024 |
|---|---|---|---|
| Sjogren's SS-A AB (RO) < =0.9 AI |
< 0.2 | Varicella Zoster IgM 0.00–0.90 index |
< 0.91 |
| Sjogren's SS-B AB (LA) < =0.9 AI |
< 0.2 |
Table 8.
Various autoimmune panel and anti-HMGCR Antibody, IgG.
| Component Latest Ref Rng |
6/21/2024 |
|---|---|
| ANTI-JO−1 AB < 20 Units |
< 20 |
| PL−7 Negative |
Negative |
| PL−12 Negative |
Negative |
| EJ Negative |
Negative |
| OJ Negative |
Negative |
| SRP Negative |
Negative |
| MI−2 Negative |
Negative |
| TIF GAMMA (P155/140) < 20 Units |
< 20 |
| MDA−5 (P140)(CADM−140) < 20 Units |
< 20 |
| NXP−2 (P140) < 20 Units |
< 20 |
| ANTI-PM/SCI−100 AB < 20 Units |
< 20 |
| FIBRILLARIN (U3 RNP) Negative |
Negative |
| U2 SNRNP Negative |
Negative |
| ANTI-U1-RNP AB < 20 Units |
< 20 |
| KU Negative |
Negative |
| ANTI-SS-A 52 KD AB, IGG < 20 Units |
< 20 |
| HMGCR Antibody, IgG 0–19 Units |
> 200 (H) |
Table 9.
Results of throat culture.
| Throat culture | 6/24/2024 |
|---|---|
| Final | No Streptococcus pyogenes (Group A) isolated |
| Final | No Streptococcus pyogenes (Group A) isolated |
Table 10.
Results of blood and urine cultures.
| Blood culture | 6/22/2024 | Urine culture | 6/22/2024 |
|---|---|---|---|
| Final | No growth at 5 days | Final | No growth at 5 days |
| Final | No growth at 5 days | Final | No growth at 5 days |
The patient had a history of extensive drug allergies, including penicillins, lisinopril, fluticasone-salmeterol, seafood, aspirin, ibuprofen, Mayonnaise, and Ketchup, with an array of causing the rashes to angioedema. On admission, it was probed that around 2 weeks ago, the patient had pain in the left 2nd upper premolar associated with swelling of the upper lip and was empirically prescribed Clindamycin for possible dental infection, which the patient was taking until the day of presentation in the ED.
The patient was put on airborne, and contact isolation for shingles and acyclovir was initiated. However, because the rash didn't evolve into macro-vesicles, pustules, and crusting, zoster was considered less likely, and isolation precautions and acyclovir were discontinued on Infectious disease consult. Considering extensive allergy history, the next DD included Rash due to drug allergy secondary to Clindamycin, which was still continued owing to possible dental infection as a physical exam showed left upper 2nd premolar swelling. Dentistry eval and imaging failed to reveal any abscess, so Clindamycin was discontinued, but doxycycline was initiated since White cell counts were trended down on antibiotics (likely there was initially a dental abscess that resolved with Clindamycin). With hydration and discontinuation of Clindamycin, statin + colchicine, the patient's CPK levels improved. The rash began to evolve into desquamating lesions. However, the patient consistently complained of pain all over the body to the point of being bed-bound (the patient at baseline was able to ambulate with support). Rheumatology was consulted, and statin-induced severe myopathy was suspected as a down-trending of CPK levels was leveling off. Anti-HMGCo antibodies were ordered and returned positive, confirming statin-induced myopathy. Statin-induced dermatomyositis was also in differentials. Although the rash didn't follow that pattern, the patient denied skin biopsy. Hence, initial generalized body pain along with rash was likely due to weakness due to statin myopathy, and the rash was secondary due to drug allergy; thereby, weakness and rash together were masquerading as a single entity of painful shingles in the setting of multiple myeloma.
The resolution of the rash is shown in Fig. 2 below.
Fig. 2.
Resolution of rash after discontinuation of offending drugs.
Discussion
Statins are one of the most widely prescribed drugs used to reduce the risk of cardiovascular events in predisposed individuals. Statins work by inhibiting HMG-CoA reductase, leading to decreased cholesterol synthesis in the body [4]. The most common side effects of statin use include musculoskeletal ranging from myalgia to myositis to life-threatening rhabdomyolysis. These are together commonly known as statin-induced myopathy [5]. The incidence of myalgia with statin use has been described to be 10–15 % in various studies [6]. Statin-induced myopathy causes muscle pain, weakness, and elevated creatine kinase (CK) levels, which may explain this patient's severe, body-wide pain and subsequent immobility. The initial labs of our patient reported elevated creatine kinase, suggesting myopathy, and the improvement in CK levels following discontinuation of atorvastatin further supports the diagnosis of statin-induced myopathy.
Herpes zoster, commonly called shingles, is caused by the reactivation of the Varicella Zoster Virus. This virus lays dormant in the sensory nerve roots for a lifetime after the initial infection. The virus can reactivate to cause a rash limited to a dermatomal pattern [7]. In individuals who are severely immunocompromised, Herpes can reactivate to cause a much more severe condition called disseminated herpes zoster. This condition can present with a diffuse rash not limited to a dermatomal pattern [8]. Herpes zoster begins with a prodrome of pain and flu-like symptoms followed by the appearance of rash. The rash begins as macules and papules on an erythematous base. The vesicles are clustered together and progress to pustules and scabs in the next week or so. The complete resolution of scabs occurs in about 2–3 weeks [9].
The patient's extensive history of drug allergies, including reactions to penicillin, lisinopril, and various other substances, adds another layer of complexity to her clinical picture. The patient developed a rash, which was first thought to be due to Herpes Zoster reactivation because of her compromised immunity due to Multiple Myeloma and the presence of microvesicles on her neck. However, the progression of the rash was not consistent with Herpes, prompting further investigations into the cause of the rash.
Clindamycin is a commonly prescribed antibiotic for intra-abdominal infections, septicemia, and gynecological infections. It works by binding the 50S subunit of the bacterial ribosome, inhibiting protein synthesis, and is, therefore, bacteriostatic [10]. The most common side effects of clindamycin are gastrointestinal, including diarrhea, nausea, and clostridioides difficile colitis. Cutaneous adverse drug reactions due to clindamycin are rare. The only cutaneous reaction reported is a rash with an incidence of < 1 %, and the cause of the rash is thought to be immediate or delayed hypersensitivity reactions [11], [12].
The severity of statin-induced myopathy increases with the increase in the dose of the drug. The cause of statin-induced myopathy is complex and includes both patient-related factors and the pharmacokinetics of statins. Various recent studies have confirmed the role of genetic variants in SLCO1B1 in the development of statin-induced myopathy [13], [14]. Statin-induced myopathy is also associated with the development of anti-HMGCo antibodies in the body. Studies have found a positive correlation between these antibodies, CPK levels, and the severity of the disease: the higher the severity of the disease, the higher the CPK and anti-HMGCo antibody levels, and vice versa [4], [15].
The treatment of both statin-induced myopathy and hypersensitivity reaction to clindamycin is the discontinuation of the offending drugs, and our patient demonstrated a significant improvement in both her body aches and rash after the removal of the drugs.
Conclusion
Drug-induced hypersensitivity may mimic a rash secondary to reactivated herpes zoster in the setting of immunocompromised status. However, a thorough history taking and physical examination can rule out the possibility of zoster rash if the patient does not depict a characteristic pattern of the lesions' vesicles, pustules, and crusting simultaneously. Statin-induced myopathy is one of the common side effects of statin ingestion. However, positive anti- HMG CoA reductase inhibitor antibodies are found in very few cases associated with immune-mediated myopathy, which gets aggravated after the use of statins. AntiHMG Coa Reductase inhibitors antibodies and Muscle biopsy are diagnostic tools to rule out dermatomyositis in immune-mediated statin-induced myopathy if a patient presents with proximal muscle weakness and concomitant rash. Discontinuation of statin can lead to considerable improvement in muscle weakness.
CRediT authorship contribution statement
Fayyaz Hafsa: Writing – review & editing, Writing – original draft, Visualization, Validation, Formal analysis, Data curation. Patil Shreyas: Visualization, Validation, Software, Resources. Kareem Hira Khalid: Writing – review & editing, Data curation, Conceptualization. Shehryar Muhammad: Supervision, Project administration, Methodology, Investigation. Ashraf Muhammad Fawad: Writing – review & editing, Writing – original draft, Visualization, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributor Information
Hira Khalid Kareem, Email: kareemh@thewrightcenter.org.
Muhammad Fawad Ashraf, Email: fawad1110@gmail.com, fawadashraf@kemu.edu.pk.
Muhammad Shehryar, Email: Shehryam@nychhc.org.
Hafsa Fayyaz, Email: hafsafayyaz98@gmail.com.
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