Photoonycholysis and a Positive ANA

This 20 year-old woman developed a painful bilateral erythema of the skin at the margins of the thumbs and index fingers.  Around two weeks later, she noticed bleeding under one thumb nail and color changes under the other thumb nail.

She was seen at a walk-in clinic where no therapy was given but a battery of blood tests were done.  Among them was an ANA which was reported as positive with a homogeneous pattern and a titer of 1:640.  Her RF, C Reactive Protein and EST were normal as well as all other tests.

The positive ANA alarmed her and her parents and she sought a dermatological opinion.

The clinical images taken 3 weeks after onset show mild erythema at the margins between dorsal and palmar skin and the nail changes.

 

Further history revealed that she had been on doxycycline for acne  when the eruption occurred.

Diagnosis:  Phototoxic drug eruption from doxycycline with photoonycholysis.  I presume the positive ANA is a "false positive."  The test should probably not have been ordered.  As an incidental finding, taken out of context it can be anxiety-provoking.

References:

1. Doxycycline-induced photo-onycholysisDidier Rabar, Patrick Combemale, François Peyron.  J Travel Med. Nov-Dec 2004;11(6):386-7.
Abstract: Because  there  is  a  widespread  resistance  to  other drugs, doxycycline is often prescribed as chemoprophylaxis for malaria. Although this drug is commonly used for the treatment of acne vulgaris, no large studies have been conducted on the safety of doxycycline. However, several side effects, especially skin and nail disorders, are induced by this drug. In this article, we report a case of photoonycholysis in a woman undergoing doxycyclineprophylaxis for malaria.

2. Photo-onycholysis   Following Two   Weeks of Doxycycline. KC S, Karn D, Shrestha S. J Nepal Health Res Counc  2016 Jan - Apr;14(32):66-8
Abstract: Photo-onycholysis is a form of phototoxic reaction characterized by spontaneous separation of the nail plate from the nail bed. It usually follows drug intake and tetracycline is a well-known culprit. We present a case of 19 years gentleman who developed this rare side effect following two weeks of ingestion of doxycycline.

3. Antinuclear antibodies in healthy people and non-rheumatic diseases – diagnostic and clinical implications. Bogna Grygiel-Górniak, Natalia Rogacka, and Mariusz Puszczewicz. Reumatologia. 2018; 56(4): 243–248.  PMID: 30237629. Free Full Text.

DPP4-Inhibitor Drug-Induced Bullous Pemphigoid

The patient is a 68 yo woman with Type II diabetes and Stage IV renal failure who presented with a four month history of intense generalized pruritus.  Her PCP had treated her for scabies without effect.  Her medications  include Lantus, lisinopril, atorvastin risperadone  and Januvia (sitaglipin).  The Januvia was the  most recent new medication and it was started a month or two before she started to itch.

O/E:  there was a wide-spread dermatitis on torso and extremities.  No frank bullae but there was a suggestion of vesicles.  No burrows were seen.  Vesicles were noted on the palms and soles.

An eliptical biopsy was done as well as a 3 mm punch biopsy from perilesional skin for DIF.

Histopath showed: Eosinophilic spongiosis and spongiotic vesiculation.
DIF was positive for IgG in a linear pattern at the DEJ
Histological Photographs courtesy of Dr. Jag Bhawan, Boston University SkinPath Laboratory

Diagnosis:  Bullous Pemphigoid secondary to DPP-4 inhibitor.  

Discussion: DPP-4 inhibitors  are a class of drugs that are used for Type 2 diabetes.  There have been eight references to BP as a cutaneous drug effect DPP-4 inhibitors in PubMed (the first was in 2016).  It is clear that we will be seeing more of these patients what with the wide-spread usage of DPP-4 inhibitors.

Acknowledgement:  Special thanks to Rick Sontheimer, M.D. who alerted me to this phenomenon and Dr. Jag Bhawan for the pathology interpretation and the beautiful photomicrographs.

References:

 1. Bullous Pemphigoid Associated with the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin in a Patient with Liver Cirrhosis Complicated with Rapidly Progressive Hepatocellular Carcinoma. Harada M et. al.  Intern Med. 2017 Sep 15;56(18):2471-2474  Free Ful Text. 

2. Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: Retrospective multicenter case-control study from France and Switzerland.  Benzaquen M, det. Al.. J Am Acad Dermatol. 2018 Jun;78(6):1090-1096

CONCLUSIONS: DPP4is, especially vildagliptin, are associated with an increased risk for development of BP. Their use needs to be carefully evaluated, particularly in high-risk patients, such as males and those age 80 years or older.  Full Abstract.

3. Vildagliptin significantly increases the risk of bullous pemphigoid: A Finnish nationwide registry study. O. Varpuluoma et. al. J. Invest Dermatol:

Volume 138, Issue 5, Supplement, Page S46, 2018.  Full Abstract (Supplied by Rick Sontheimer) 

Painful Finger Tips Secondary to Opdivo

The patient is a 65-year-old woman with metastatic lung cancer who presents for evaluation of painful fingertips.  She has also had marked axillary pruritus which she handles with Lotrisone spray. 

Her medications include metformin, two types of insulin, metoprolol, Lipitor, Lexapro, and irbesartan.  Recently, she has been started on Opdivo (nivolumab) every two weeks.  Within a few months of starting Opdivo, she developed intense axillary pruritus, and a month or so later, intensively painful fissuring of the fingertips.  Each treatment of Opdivo re-exacerbates the fingertip problem, which is unbearable. Her cancer has gone into remission and she feels well otherwise.  She especially enjoys her grandkids.

Her oncologist put her on prednisone 20 mg q.i.d. for the fingertip eczema.  Because of the patient's diabetes, her fasting blood sugars while on prednisone have gone up over 500 mg%. 

EXAMINATION:  The examination shows erosions on a few of the fingertips without erythema.  Her feet and axillae are normal.  

Clinical Photos:

We did a literature search and there are a few early reports of dermatitis with Opdivo but they do noot not affect the hands.  It may be too early to say; but given the literature on painful hands and feet related to cancer therapies this is probably a significant reaction.  

PLAN:  I would try to keep this simple and avoid the prednisone.  Start with wet soak for 20 minutes in warm water, followed by clobetasol ointment, followed by gloves (a modified Soak and Smear protocol).  We will see how she does with this.  I have the patient's permission to post her case on this site where we may get ideas and/or be of help to others with a similar problem.   There is a reference to preventing Hand Foot reactions with chemotherapy.  It seems that Celebrex (celecoxib) may be the best option. Note: Celecoxib has been reported to be associated with an increased incidence of heart attack and stroke.  It's use should not be cavalier.

References:.

1. Survey of cutaneous adverse reactions to targeted cancer therapies: value of dermatological advice. Damiani G OncoSkin working group. G Ital Dermatol Venereol. 2018 May 11. Abstract: From June to October 2012, 25 patients with cutaneous adverse reactions linked to targeted therapies were included in the study. The main prescribed drugs were cetuximab (52%) and erlotinib (20%) and the most common reactions were folliculitis/pustules (40%) and rash/erythema (40%). Hand-foot reaction syndrome was present in 8% of patients. A total of 30% of patients treated for a cutaneous reaction underwent a consultation by a dermatologist. In these patients the rate of oncologic therapy continuation without regimen modifications was higher (100%), while it was progressively lower in patients treated by oncologists (71%) or without any specific treatment (60%). Adverse reaction should be recognized by both dermatologists and oncologists and a multidisciplinary approach is mandatory.

2. Prevention strategies for chemotherapy-induced hand-foot syndrome: a systematic review and meta-analysis of prospective randomised trials.

Macedo LT, et.al. Support Care Cancer. 2014 Jun;22(6):1585-93.

Abstract

Amongst 295 studies identified, only ten met the inclusion criteria. Celecoxib prevented both moderate to severe (odds ratio [OR] 0.39, 95 % confidence interval [CI] 0.20-0.73, P = 0.003) and all-grade HFS (OR 0.47, 95 % CI 0.29-0.78, P = 0.003), whereas pyridoxine and topical urea/lactic acid formulations failed to prove efficacy. There were no proven benefits in mild HFS. The use of topical antiperspirant has not been shown to improve results, according to a single trial.

Drug-Induced Lupus?

There are more things in heaven and earth then I dreamt of in our philosophy; and more things that we encounter in our offices than we can find in PubMed’s> 20,000.000 citations.

 A 35-year-old woman was started on a second course of isotretinoin for recurrent acne. Her previous treatment was two years earlier and was uneventful.  A few weeks after restarting the medication, at a dose of 0.5 mg per kilogram per day, she experienced some malaise, muscle aches, and mild joint pain. There were no new skin findings. She called me and I allowed that I had not heard of these symptoms with isotretinoin, but ordered a CBC and an ANA.

The CBC was normal, but the ANA was positive at 1:640 with a homogeneous pattern.   A PubMed search retrieved no references to drug-induced lupus and isotretinoin. However, a Google search found some anecdotal reports and a few cases of suspected DIL with isotretinoin (there were 5 alleged cases of DIL out of 27,831 self- reported isotretinoin side-effects) eHealthme.

With regards to our patient, I am going to repeat her ANA and obtain an anti-histone antibody test. If the ANA is still positive I will have her stop the isotretinoin and repeat the lab studies after 2–3 weeks. Should this likely be DIL then I think it is important that there be a report in the medical literature as undoubtedly other patients will experience this.

Statin-related Pityriasis Rubra Pilaris

Abstract:  A 67 year-old man developed a generalized dermatitis 2 weeks after starting pravastatin. 

HPI:  This previously healthy 67-year-old man developed a scaly eruption on his forehead approximately 10 to 14 days after starting pravastatin.  While his lipid profile was not very worrisome his PCP recommended the statin based on new guidelines.  The eruption spread and generalized over the next one to two weeks when he stopped the statin.

O/E:  He presented with a generalized process.  This had features of an erythroderma with islands of sparing.  There is a marked palmoplantar hyperkeratosis with desquamation. There was an early ectropion of the lower eyelids. There is no lymphadenopathy.

Clinical Photos:

Lab: CBC and CMP are within normal range, need lipid profile

Microscopic Images:
Photomicrographs courtesy of Hyejin Leah Chung, M.D. Dermatopathology at Boston University

H&E x 200

Alternating orthokeratosis and parakeratosis in both vertical and horizontal directions, a few scattered keratinocytes with perinuclear vacuolization

H&E x 100

Follicular plugging with foci of parafollicular parakeratosis, subtle regular acanthosis with a rounded lower border

Diagnosis:  Most likely statin related PRP

Questions:  Is acitretin the drug of choice in this clinical situation?  Is it preferable to isotretinoin?

References:

1) Gajinov ZT, et al. Drug-related pityriasis rubra pilaris with acantholysis. Vojnosanit Pregl. 2013; 70(9):871-3.

2) Dicken CH. Treatment of classic pityriarsis rubra pilaris. J Am Acad Dermatol. 1994; 31(6):997-9 

3) Adult pityriasis rubra pilaris: a 10-year case series.

Clayton BD1, Jorizzo JL et. al J Am Acad Dermatol. 1997 Jun;36:959-64.

Abstract

BACKGROUND:

Pityriasis rubra pilaris (PRP) often has a devastating impact on the lives of patients. Descriptions of its histopathologic features are not uniform. Finding a successful therapy can be challenging.

OBJECTIVE:

Our purpose was to examine the histopathologic features and response of patients to our standard therapy of an oral retinoid and concomitant or later addition of low-dose weekly methotrexate.

METHODS:

A retrospective chart review was done on 24 patients with PRP seen from March 1986 to March 1996. Biopsy specimens from 19 patients were reexamined. Telephone follow-up was conducted to determine maintenance of remission.

RESULTS:

All patients had the adult acquired form of PRP. Biopsy specimens from nine patients were characterized by prototypical findings of PRP, while the others included both typical and other features. Twenty-two patients were treated with either isotretinoin, 40 mg twice daily, or etretinate, 25 to 75 mg/day. Six patients with more disabling involvement had low-dose weekly methotrexate ranging from 5 to 30 mg started concurrently. Five patients had weekly methotrexate added at a later time. Seventeen patients showed 25% to 75% response after 16 weeks of therapy. All patients whose skin cleared maintained their remission.

CONCLUSION:

Initial oral retinoid plus concurrent or later low-dose weekly methotrexate resulted in 25% to 75% improvement of PRP in 17 of 24 patients after 16 weeks of therapy. Some of the atypical features seen in biopsy specimens emphasize the importance of clinical and histopathologic correlation in establishing the diagnosis.

Toxic Erythema

Presented by Dr. Henry Foong,

Ipoh, Malaysia

Abstract:  41 yo man with short history of toxic erythema

HPI: The patient is a 41 yr old restaurant worker who presented with 5 day history of bilateral and symmetrical erythema over the loins, groins and knees.

About a week ago, he had a furunculosis on upper back and was prescribed Augmentin. Two days later he developed high fever and was treated with ciprofloxacin by a physician. A day later he noticed itchy rashes on both thighs and since then, the macular erythema spread symmetrically to the loins, upper shoulders and knees.  He has no fever.

His past medical history was non-contributory.

Examination showed bilateral and symmetrical diffuse erythema on the thighs, knees, loins and upper shoulders. Over the loins, there was symmetrical and bilateral edematous areas  with vesicles over a background of erythema.  His scalp, oral cavity and genitalia were clear.

Clinical Photos:

Lab: Culture and a skin biopsy has been done. Culture negative.  Biopsy pending.

 TWBC 3200 (N 85.1%  L 10.3%  E0 .5%  M3.4%  B 0.8%)  ESR 36

Diagnosis: Toxic erythema

Differentials:  Streptococcal/Staph cellulitis 

Questions and Comments:  The presence of blisters /edema on the loin is worrying.  In the meantime what would you recommend for this patient? Would you use corticosteroids in this patient? I have stopped both augmentin and ciprofloxacin. In terms of dressing, I used wet compress with dil. KMNO4.Have I missed anything?

References:

1.  Miyahara A, et. al.  A new proposal for a clinical-oriented subclassification of baboon syndrome and a review of baboon syndrome. Asian Pac J Allergy Immunol. 2011 Jun;29(2):150-60

Source: Department of Pediatrics, Tokyo Medical University. miyahara.pediatrics@gmail.com

Abstract

OBJECTIVE: To review baboon syndrome (BS). Data Sources: Date sources were obtained from PubMed and Google Scholar: Photographs of baboon syndrome were obtained from our patient.

STUDY SELECTIONS: PubMed and Google Scholar were searched up to June 30, 2010. The search terms were "baboon syndrome", "SDRIFE" and "thimerosal allergy". Reverse references from relevant articles and Google Scholar were also used. As BS is a classical disease and cases of offending agents were relatively old, some references were more than five years old. In order to gather as many cases of offending agents as possible, more than 50 references were collected.

RESULTS AND CONCLUSION: We divided BS into as 4 groups; classical baboon syndrome, topical drug-induced baboon syndrome, systemic drug-induced baboon syndrome and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). The pathomechanism of BS is still unknown. A delayed type of hypersensitivity reaction, a recall phenomenon, pharmacologic interaction with immune-receptors and anatomical factors may be involved in the causation of BS.  This valuable article is available in Free full text

2. Tan SC, Tan JW.  Symmetrical drug-related intertriginous and flexural exanthema. Curr Opin Allergy Clin Immunol. 2011 Aug;11(4):313-8.

Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore, Singapore. Sze_Chin_Tan@ttsh.com.sg

Abstract

PURPOSE OF REVIEW: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), previously termed drug-related baboon syndrome, is a benign and self-limiting type IV hypersensitivity reaction characterized by symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. It may also occur in the absence of previous drug exposure.

RECENT FINDINGS: Antibiotics, in particular beta-lactams, comprise the majority of causes of SDRIFE. Other drugs which have been implicated include antihypertensives, radiocontrast media, chemotherapeutic agents, and biologics. Histology of lesional skin is variable with predominance of superficial perivascular inflammatory cell infiltrates. Outcomes of allergy tests are variable with positive delayed intradermal tests reported for penicillin V, allopurinol; positive patch tests for erythromycin, mitomycin, nystatin, pseudoephdrine; positive lymphocyte transformation tests for erythromycin; and positive drug provocation tests for clindamycin, cimetidine, corticosteroids, terbinafine, and valacyclovir.

SUMMARY: Diagnosis of SDRIFE is dependent upon recognition of the clinical morphology and distribution of the rash, and its temporal relationship to the use of the suspected drug. Outcomes of in-vivo and in-vitro tests have been inconsistent, and thus may not be useful in the identification of the putative drug.

35 yo woman with short history of urticarial vasculitis

Abstract: 35 yo woman with three day history of an atypical urticarial eruption

HPI: This 35 yo woman developed an urticarial eruption 8 - 10 days after starting amoxicillin for a dental infection.  At first the lesions blanched with pressure but over the last few days before her office visit the some of the lesions looked hemorrhagic.  She had mild arthralgias but no fever or malaise.

O/E: There was a wide-spread eruption mostly on legs and arms.  On her thighs the lesions appeared hemorrhagic.  The torso, head and neck were mostly spared.

Clinical Photos:

Pathology:  Two 4 mm punch biopsies were obtained from the thighs.  There was a superficial and mid dermal mixed inflammatory infiltrate composed mostly of neutrophils and eosinophils with a few lymphocytes.  The pathology was read as leucocytoclastic vasculitis vs. urticarial vasculitis.
Photomicrographs are 10x, 20x, 40x and courtesy of Dr. Jag Bhawan

Lab:  CBC nl; Chem panel nl; UA nl

Diagnosis:  Most consistent with Drug-Induced Urticarial Vasculitis (UV).

Discussion:  While UV is recognized to present as a cutaneous drug eruption, MEDLINE has no reports of UV from amoxicillin.  In this otherwise healthy woman, this seems to be the best diagnosis.  She was treated with prednisone 20 mg b.i.d. and at one week her skin lesions had completely resolved.  The dose was dropped to 20 mg per day for the second week and then she will stop.  We are aware of cases of presumably drug-induced UV which can last for weeks to months and be associated with hypocomplementemia and positive ANA and antihistone antibodies. Since this woman did well and her process resolved quickly more specialized tests were not done.

Questions:
I don't feel any further work-up is indicated at this point.  If she stays clear the case is probably closed.  If she continues to have UV-like lesions once prednisone is discontinued, a more in-depth work-up will be initiated.  Does anyone feel we should be more aggressive?

Reference:
1. eMedicine.com  Urticarial Vasculitis
2. There are no reports of UV from amoxicillin and only one with ampicillin but it is very vague.

Note:  I will ask the patient to add her comments.

Teledermatology Rules: Vasculitis

Abstract: 2o yo man with one week history of palpable purpura.
HPI: This 20 yo college student was started on isotretinoin for severe cystic acne a month before he developed a rash on his legs. He also had an upper respiratory infection two weeks before the eruption began. He is away at school (a two hour drive). His mother called the office and spoke to my secretary. Busy week. When I heard that he had a rash, I relayed the message that it was probably the common dermatitis we see with patients on isotretinoin and if worried to send me a photo. Two days later, this photo was sent:


The patient was then emailed and asked to come in the next day. Labs were ordered done before the visit.

O/E: Palpable purpura both L.E. Right ankle swollen and tender. Patient limping.

Lab: CBC normal, UA normal. Pending Labs: Throat culture, ANA, ASOT. (Hep C, Stool for OB, not ordered)

Path: Biopsy performed. Not back

Diagnosis: Leucocytoclastic vasculitis. Etiology: The URI, isotretinoin, idiopathic

Plan: Rest for a few days. No specific therapy at this time except stopping the isotretinoin. If he improves uneventfully without evidence of GI or renal involvement will offer a re-challenge with isotretinoin.

Discussion: A few cases of LCV have been reported with isotretinoin. This patient has severe cystic acne with scarring and it would be a shame to withhold drug if it were not putative for the LCV. I admit I did not pay proper attention to the first telephone call. This illustrates the power of teledermatology which can be almost standard in a few years as cell phone cameras become better and people know how to use them more adroitly.

Questions: What are your thoughts and suggestions?