DRESS Syndrome With Autoimmune Hepatitis From Strontium Ranelate
Strontium ranelate, which is used for postmenopausal osteoporosis, has been associated with drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, a severe, acute, potentially fatal, multisystem adverse drug reaction characterized by skin rash, fever, hematological abnormalities, and lymphadenopathy with involvement of several internal organs. We report the case of a woman who developed DRESS syndrome with a generalized maculopapular rash, eosinophilia, dyspnea, bilateral cervical lymphadenopathy, and reactivation of Epstein-Barr virus (EBV) with liver damage 3 weeks after administration of strontium ranelate for postmenopausal osteoporosis. Approximately 6 months after total remission of cutaneous symptoms, the patient developed autoimmune hepatitis. This case confirms that strontium ranelate should be considered as a possible factor in the etiopathology of DRESS syndrome as well as in the subsequent development of autoimmune hepatitis. The possibility of developing autoimmune hepatitis as a part of DRESS syndrome related to strontium ranelate use can occur months after the acute episode.
Practice Points
- Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome refers to a severe, acute, potentially fatal, multisystem adverse drug reaction characterized by skin rash, fever, hematological abnormalities, and lymphadenopathy with involvement of several internal organs.
- Strontium ranelate should be considered as a possible factor in the etiopathology of DRESS syndrome and in the development of autoimmune hepatitis as a part of DRESS syndrome.
The patient was given another dose of steroids (prednisolone 25 mg daily). Liver function normalized within 1 month (aspartate aminotransferase levels went from 195 U/L to 21 U/L; alanine aminotransferase went from 324 U/L to 21 U/L; γ-glutamyltransferase went from 268 U/L to 63 U/L). The patient is currently taking a maintenance dose of prednisolone 5 mg and has normal liver function.
Comment
Uses of Strontium Ranelate
Strontium ranelate is recommended for reducing the risk for fracture in postmenopausal women 70 years and older with a bone mineral density T-score of –3.0 or lower (ie, primary prevention) as well as for the treatment of morphometric vertebral fracture in established postmenopausal osteoporosis (ie, secondary prevention). Strontium ranelate has a dual action that includes increasing bone formation and reducing bone resorption, leading to rebalancing of bone remodeling in favor of bone formation. Strontium ranelate was shown to increase the recruitment and activity of osteoblastic cells and to inhibit the recruitment and activity of osteoclasts.2 The recommended dose of oral strontium ranelate is 2 g once daily.
Side Effects of Strontium Ranelate
In a 3-year study of side effects associated with strontium ranelate, severe reactions were described in 23% of the reported adverse effects in 844 patients.3 In this study, cardiovascular effects, particularly thromboembolism, and DRESS syndrome were the most frequent side effects. Since its introduction in the market, at least 16 cases of DRESS syndrome related to strontium ranelate use have been reported in Europe, including 2 fatal cases.2 Two deaths have been reported to be associated with this drug,2 which was the basis of the warning document by the European Medicines Agency regarding the risk for strontium ranelate inducing DRESS syndrome.4
Development of DRESS Syndrome
The most common agents involved in DRESS syndrome are anticonvulsants, sulfonamides, dapsone, minocycline, allopurinol, and gold salts, as well as celecoxib, antituberculosis drugs, nonsteroidal anti-inflammatory drugs, antibiotics, calcium channel blockers, and antiretroviral drugs.5,6 The mortality rate of DRESS syndrome is 10%.6
The pathophysiology of DRESS syndrome is still unclear. Altered drug metabolism, genetic predisposition, and concomitant infection or reactivation of bacterial or viral infection (eg, HHV-6, EBV, CMV, human immunodeficiency virus, influenza, viral hepatitis) could be factors leading to development of DRESS. Autoimmune or connective-tissue diseases also have been suggested to increase the risk.7
Clinicians should suspect DRESS syndrome in any patient developing a rash 3 to 6 weeks after starting drug therapy. This disorder often starts with fever (temperature >38°C) and includes cutaneous symptoms such as generalized rash that may progress to exfoliative dermatitis. There usually is involvement of one or several internal organs with the development of hepatitis; interstitial pneumonia; interstitial nephritis; myopericarditis; myositis; pancreatitis; thyroiditis; and hematological abnormalities, primarily eosinophilia or atypical lymphocytosis. Facial edema and lymphadenopathy also may be present. A skin biopsy can confirm the clinical diagnosis of DRESS syndrome but is not specific because cutaneous histologic patterns often show a lymphocytic infiltrate that sometimes mimics cutaneous lymphoma. Other diseases that DRESS syndrome may mimic include Stevens-Johnson syndrome and toxic epidermal necrolysis as well as Kawasaki disease, Still disease, acute viral infections, idiopathic hypereosinophilic syndrome, and lymphoma, which should be excluded from the differential diagnosis.8
Diagnosis of DRESS Syndrome
There is no gold standard for the diagnosis of DRESS syndrome. In our case, the diagnosis of DRESS syndrome was based on the RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions to Drugs) score as described by Kardaun et al,9 which grades DRESS syndrome cases as excluded (<2 points), possible (2–3 points), probable (4–5 points), or definite (>5 points) based on the following clinical criteria: fever (temperature >38.5°C; from a minimum of –1 point if absent to a maximum of 0 points if present); enlarged lymph nodes (from a minimum of 0 points if absent to a maximum of 1 point if present); eosinophilia (0 points if absent, 1 point if 10%–19% or 700–1500 μL, 2 points if ≥20% or >1500 μL); atypical lymphocytes (from a minimum of 0 points if absent to maximum of 1 point if present); skin involvement with rash (1 point if >50% of body surface area is involved, 1 point if there is a maculopapular rash, 1 point if skin biopsy suggests DRESS syndrome); organ involvement (1 point each for liver, kidneys, lungs, muscle/heart, pancreas, and other organs); resolution in at least 15 days (from a minimum of –1 point if absent to maximum of 0 points if present); and evaluation of other potential causes measuring antinuclear antibodies, blood culture, and serology for hepatitis virus (A–C), chlamydia, and Mycoplasma (1 point if 3 or more are negative and none positive). Virus reactivation also should be considered a main characteristic of DRESS syndrome. Therefore, its prevalence is not homogenous, so the absence of viral reactivation cannot be considered exclusion criteria. Several case reports and a few well-documented series have evidenced markers of virus reactivation in many cases of DRESS. Herpes simplex virus 6, CMV, and EBV are the most frequently reactivated.
