Hydralazine Induced Vasculitis Ashley Keyes, MD

PMH cardiomyopathy and CKD Admitted for progressively worsening shortness of breath

ROS notable for 18 months hoarseness and approximately 10 lb weight loss 1st week of hospitalization complicated

1st week of hospitalization complicated by hypotension and AMS -> MICU

Day 8, Dermatology consulted for right forearm cellulitis To our surprise, he had many more skin findings, all of which his family confirmed developed in house

As you may now be thinking, his skin exam surprised us

Acral pseudoembolic vesiculopustules

Critical care Nephrology Infectious Disease Rheumatology

Evaluation Infection? Blood, urine and sputum cultures Tissue culture A first thought. The patient was critically ill with a rising leukocytosis and skin findings consistent with septic emboli. However, he remained afebrile, all cultures were negative and he was unresponsive to antibiotics. ? Infective endocarditis

Evaluation Malignancy? Imaging Could a paraneoplastic process explain everything? As mentioned, he had hoarseness and weight loss. Earlier in admission, head and neck team performed endoscopy with friable masses on the vocal cords. CT of the chest showed pulmonary nodules.

Evaluation Inflammatory? Biopsy ESR, ANA, AHA, ANCA Lastly, we couldn’t ignore the possibility of an inflammatory process. In fact, our service saw a case of ANCA+ vasculitis earlier in the year with strikingly similar cutaneous features. The culprit? Hydralazine. We obtained a biopsy and sent serologies. While awaiting the results, a review of home medications included hydralazine. Due to hypotension, all anti-hypertensives had been discontinued prior to our consultation.

Laboratory ESR – 116 ANA – 1:320 Histone antibody – 3.0 (0 - 0.9) Myeloperoxidase antibody – 99 (0 – 19) Protease 3 antibody- 165 (0 – 19) ANA – Diffuse Strongly positive by our labs standards Complement, RF, SSA, SSB, RNP and smith negative *1 month later histone 2.4, myeloperoxidase 98 and protease 3 78

Necrotizing deep seated thrombotic process with ischemic necrosis of the eccrine coil and endoneurium

The biopsy was also notable for extravascular neutrophilia in immediate apposition to the vessels. These findings with the characteristic clinical presentation lead us to the diagnosis of hydralazine-induced vasculitis.

Hydralazine Induced ANCA Vasculitis

I’ll briefly show images of our first case of hydralazine induced vasculitis. While our patient had predominantly pulmonary and renal involvement, her course as complicated by gastrointestinal bleeding, an even more rare presentation. Acral pseudoembolic vesiculopustules with necrotic ulcerations

Hydralazine Induced - ANCA+ Vasculitis Lupus Erythematosus Prevalence Rare 5-10% Clinical presentation Constitutional symptoms and shortness of breath Fever, arthralgias, myalgias and serositis Target organ systems Renal, pulmonary, gastrointestinal, integumentary Musculoskeletal, integumentary Antibody profile ANA, AHA, ANCA* *Myeloperoxidase, human leukocyte elastase and lactoferrin ANA, AHA, ANCA Treatment Medication cessation +/-systemic immunosuppression Medication cessation Prevalence – Case reports of 13 cases. 5.4% 100 mg daily for >3 years and 10.4% 200 mg daily for >3 years Clinical presentation – Inspient onset with sudden rapid decline Target organ systems are the most defining features – Skin manifestations include cutaneous vasculitis with hemorrhagic bullae with acral and mucosal predilection vs classic cutaneous manifestations of lupus. Renal involvement is uncommon in DILE. Antibody profile – Upon first glance they appear similar. In drug induced vasculitis, the patient produces ANCA against more than one antigen including myeloperoxidase, human leukocyte elastase and lactoferrin Treatment – Medication cessation alone is sufficient for resolution in DILE; however, severity of illness in ANCA+ vasculitis necessitates systemic immunosuppression

As with idiopathic ANCA vasculitis, the pathogenesis is unclear *As with idiopathic ANCA vasculitis, the pathogenesis is unclear. What do we know? Out of 250 patients with +MPO over a 4 year period, they investigated the use of particular medications in 30 of these patients with the highest titers. 33% exposed to hydralazine and 10% propylthiouracil All had features of idiopathic ANCA vasculitis Their data also suggests coexistence of anti-MPO with anti-elastase and/or antilactoferrin may be characteristic of drug induced ANCA vasculitis. *We did not check these in our patient.

Conclusions Mucosal and acral predilection Consider medications Promptly discontinue causative drug and initiate systemic immunosuppression As dermatologist, we can contribute by recognizing these characteristic cutaneous findings. Consider medications, perhaps especially if high titer antibodies

References Agarwal G, Sultan G, Werner, SL, Hura C. Hydralazine Induces Myeloperoxidase and Proteinase 3 Anti-Neutrophil Cytoplasmic Antibody Vasculitis and Leads to Pulmonary Renal Syndrome. Case Reports in Nephrology. 2014. Bernstein RM, Egerton-Vernon J, Webster J. Hydralazine-induced cutaneous vasculitis. Br Med J 1980;280(6208):156-157. Cambridge G, Wallace H, Bernstein RM, Leaker B. Autoantibodies to myeloperoxidase in idiopathic and drug-Induced systemic lupus erythematosus and vasculitis. Br J Rheumatol. 1994;33(2):109-114. Finlay AY, Statham B, Knight AG. Hydralazine-induced necrotising vasculitis. Br Med J (Clin Res Ed). 1981;282(6277):1703-1704.

References Kalra A, Yokogawa N, Raja H, et al. Hydralazine –Induced Pulmonary-Renal Syndrome: A Case Report. American Journal of Therapeutics. 2012; e136-138. Keasberry J, Frazier J, Isbel NM, Van Eps CL, Oliver K, Mudge DW. Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis presenting with a vasculitic syndrome, acute nephritis and a puzzling skin rash: a case report. J Med Case Rep. 2013;7(1):20. Nässberger L, Hultquist R, Sturfelt G. Occurrence of anti-lactoferrin antibodies in patients with systemic lupus erythematosus, hydralazine-induced lupus, and rheumatoid arthritis. Scand J Rheumatol. 1994;23(4):206-210. Peacock A and Weatherall D. Hydralazine-induced necrotising vasculitis. Br Med J (Clin Res Ed) 1981;282(6270):1121-1122 Marina, Vamsee Priya, Malhotra, Deepak. Hydralazine-induced ANCA vasculitis with pulmonary renal syndrome: a rare clinical presentation. Int Urol Nephrol. 2012; 44: 1907-1909.

References Sangala N, Lee RW, Horsfield C, Goldsmith DJ. Combined ANCA-associated vasculitis and lupus syndrome following prolonged use of hydralazine: a timely reminder of an old foe. Int Urol Nephrol. 2010;42(2):503-506. Short AK, Lockwood CM. Antigen specificity in hydralazine associated ANCA positive sys- temic vasculitis. QJM. 1995;88(11):775-783. Yokogawa N and Vivino FB. Hydralazine-induced autoimmune disease: comparison to idiopathic lupus and ANCA-positive vasculitis. Mod Rheumatol. 2009;19(3):338-347.

Thank you!