Further dermatologic observations in cystic fibrosis

By Warren R. Heymann, MD, FAAD
Aug. 6, 2025
Vol. 7, No. 31

Holmes: Quite so. You see, but you do not observe...

– Sherlock Holmes in “A Scandal in Bohemia” (1891, written by Sir Arthur Conan Doyle)

This commentary salutes Schwartzman et al., who propose a unifying concept to long-standing observations of rashes and episodic arthritis in patients with cystic fibrosis (CF), naming the constellation of features the “cystic fibrosis dermatitis arthritis syndrome” (CF-DAS). (1)

CF is an autosomal recessive disorder of exocrine gland function that most commonly affects those of Northern European descent at a rate of 1:3500. Clinically, it is manifested by chronic sinopulmonary infections and pancreatic insufficiency. The most common cause of death is end-stage lung disease. CF is caused by a genetic mutation on chromosome 7 that codes for the transmembrane conductance regulator (CFTR) protein, which functions as a transmembrane cAMP-activated chloride channel. The most common mutation is delta F508, found in two-thirds of all cases worldwide. Despite the new class of medications known as CTFR modulators, most patients succumb to end-stage lung disease around the fourth decade of life. Dermatologic features of CF include “salty sweat,” aquagenic wrinkling of the palms (aka by many other terms, including transient reactive papulotranslucent acrokeratoderma of the palms), nutritional deficiency dermatoses (acrodermatitis enteropathica secondary to zinc deficiency, kwashiorkor from protein malnutrition, and essential fatty acid deficiency) due to malabsorption from pancreatic insufficiency, and vasculitis. (2,3)

Digital clubbing may be seen in 75% of CF patients, being inversely correlated with oxygen partial pressure in arterial blood — it is recognized as a predictor of increased mortality and premature death in patients with CF. (4) According to Smith et al., in a group of 15 patients with CF undergoing treatment with elexacaftor/tezacaftor/ivacaftor (Trikafta) for 3 months, “patients showed a clinically significant decrease in clubbing severity. This finding adds to the growing body of evidence demonstrating the efficacy of CFTR modulator therapy on the various cutaneous manifestations of CF.” (5)

Triple-combination therapy with elexacaftor, tezacaftor, and ivacaftor is approved for cystic fibrosis patients with at least one F508del mutation in the CFTR gene. (6) Triple-combination therapy has revolutionized the treatment of CF, leading to increased lung and pancreatic functioning, improved quality of life, and decreased mortality. The correctors, elexacaftor and tezacaftor, bind to defective CFTR proteins to stabilize the structure and deliver it to the cell surface. In contrast, potentiators such as ivacaftor bind to the CFTR protein at the cell surface, holding the channel open longer. (5) Cutaneous adverse reactions to triple-combination therapy are rarely reported, with most being urticarial eruptions. Li Pomi et al reported two cases of Malassezia folliculitis following triple-combination therapy — both rapidly responded to oral fluconazole without discontinuing the triple therapy. (6)

Two forms of joint disease are well-recognized in CF patients, initially classified as CF-associated episodic arthritis and the less common hypertrophic pulmonary osteoarthropathy (HPO), which characteristically flares in concert with pulmonary CF exacerbations. (7) Lampert et al. reported the case of a 28-year-old man with CF who presented with episodes of elbow joint pain and cutaneous nodules on the elbows. The nature of the nodules is obscure — no biopsies were performed. (7)

The following is the summation of the case reports defining CF-DAS. “Our patients were females (range 9–26 years) who presented with recurrent, episodic, pink papules, plaques, and nodular eruptions with individual lesions lasting 5–7 days associated with arthralgias, and in two cases arthritis. These eruptions did not have an obvious temporal association with pulmonary exacerbations. Skin lesions were sometimes pruritic but not painful. Distribution was predominately acral, involving bilateral upper and/or lower extremities. Arthralgias were severe and associated with tenderness, edema, and limited range of motion. Laboratory findings included elevated inflammatory markers, negative rheumatoid factor (RF), and absent or low-titer antinuclear-antibody (ANA). Histopathologic findings were variable and on a spectrum including perivascular and interstitial neutrophilic infiltrates with an urticarial pattern (neutrophilic urticarial dermatitis), neutrophilic eccrine hidradenitis, and small vessel vasculitis. Two patients trialed antihistamines prior to presentation with mild to no relief. All four patients were managed with supportive nonsteroidal anti-inflammatory drugs (NSAIDs). One patient was managed with prednisone followed by oral dapsone and improved significantly. This patient remains on long-term dapsone for greater than 1 year. Her rash and arthralgias flared intermittently upon discontinuation of the medication.” Although the pathophysiology of CF-DAS is unknown, the authors hypothesize that it is analogous to the bowel-associated dermatosis-arthritis syndrome [BADAS] in which immune complexes form due to chronic bacterial colonization of the respiratory tract (as opposed to the gastrointestinal tract in BADAS). (1) There may be more to the story — neutrophil function in CF demonstrates significantly altered migratory responses, cell-to-cell clustering, and microbe containment. (9)

The authors distinguish the rash of CF-DAS from urticarial vasculitis because the former lacks ecchymotic change and does not heal with hyperpigmentation. They emphasize that “recognition of CF-DAS is critical to avoid misdiagnosis and potential erroneous withdrawal of a suspected medication.” (1)

While I applaud Schwartzman et al. for defining CF-DAS, more Sherlockian efforts are needed to confirm their findings as this was a case series of only four cases. Perhaps future patients display a hint of purpura in their lesions — would these patients be classified as CF with urticarial vasculitis or CF-DAS? The prudent approach is to recognize CF-DAS as an entity while being certain that other causes of urticaria, urticarial vasculitis, or leukocytoclastic vasculitis are ruled out.

Point to Remember: The Cystic Fibrosis Dermatitis Arthritis Syndrome should be suspected in young (mostly female) cystic fibrosis patients presenting with episodic arthritis and rash.

Our experts’ viewpoint

Barrett Zlotoff, MD, FAAD
EP Cawley Endowed Professor
Director of Pediatric Dermatology
Department of Dermatology
University of Virginia

Gabrielle Schwartzman, MD
Resident Physician
Department of Dermatology
University of Virginia

Dr. Edgar “Ben” Smith (1932-2005) was my program director at the University of New Mexico. He was a Fulbright Scholar who trained in dermatology at Brooke Army Hospital. In 2020 he was inducted into the Dermatology Hall of Fame. He was also the author of Sherlock Holmes and Dermatology. (10) Ben was a member of the Baker Street Irregulars, and the founder of the Sir James Saunders Society, “Dermatologists Devoted to Detection” (it was named for a dermatologist consulted by Sherlock Holmes in “The Adventure of the Blanched Soldier”). Dr. Smith instilled in trainees a love of the hunt. And this clinical observation gave us the thrill.

As a UVA resident, Dr. Guffey noticed we had a couple of patients — young females with cystic fibrosis and painful joints — manifesting episodes of polymorphous red to purple urticarial papules, plaques, purpuric linear streaks usually concentrating around joints, but sometimes generalizing. After a Sherlockian investigation into the non-dermatologic literature, we found several similar cases. Authors have postulated, but not proven, a relationship to antigen antibody complexes from the microbially colonized lungs of cystic fibrosis patients. (11,12) We found more patients once we started looking (as one does).

The lessons — pay attention to patients and the old literature. Those with the privilege to train under Dr. Smith learned them well. He taught us that academic dermatology is a wonderful way for sleuths to make a living... Every trainee has new vision, unfettered by dogma, while the faculty sees through eyes of old mentors. We converse about old and new mysteries in the literature. It’s all great fun.

“Education never ends, Watson. It is a series of lessons, with the greatest for the last.” – Sir Arthur Conan Doyle

References

1. Schwartzman G, Zlotoff BJ, Gru AA, Guffey DJ. Cystic fibrosis dermatitis arthritis syndrome: A series of four cases. Pediatr Dermatol. 2025 Jan-Feb;42(1):133-135. doi: 10.1111/pde.15727. Epub 2024 Aug 8. PMID: 39117496; PMCID: PMC11781019.

2. Heymann WR. A new wrinkle in the diagnosis of cystic fibrosis. Dermatology World Insights and Inquiries, March 23, 2022, Vol. 4, No. 12. https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2022/new-wrinkle-diagnosis-cystic-fibrosis

3. Smith AD, Schwartzman G, Lyons CE, Flowers H, Albon D, Greer K, Lonabaugh K, Zlotoff BJ. Cutaneous manifestations of cystic fibrosis. J Am Acad Dermatol. 2024 Sep;91(3):490-498. doi: 10.1016/j.jaad.2024.04.052. Epub 2024 Apr 30. PMID: 38697219.

4. Hill RC, Axler E, Lipner SR. Digital clubbing in cystic fibrosis: The nails as clues to advanced disease. J Am Acad Dermatol. 2024 Nov;91(5):e133-e134. doi: 10.1016/j.jaad.2024.06.075. Epub 2024 Jul 9. PMID: 38992504.

5. Smith AD, Schwartzman G, Lyons CE, Flowers H, Albon D, Greer K, Lonabaugh K, Zlotoff BJ. Response to Hill et al, "Digital clubbing in cystic fibrosis: The nails as clues to advanced disease". J Am Acad Dermatol. 2024 Nov;91(5):e135. doi: 10.1016/j.jaad.2024.07.008. Epub 2024 Jul 9. PMID: 38992503.

6. Li Pomi F, Di Bartolomeo L, Vaccaro M, Lentini M, Cristadoro S, Lucanto MC, Lombardo M, Costa S, Borgia F. Malassezia Folliculitis following Triple Therapy for Cystic Fibrosis. Medicina (Kaunas). 2022 Sep 2;58(9):1204. doi: 10.3390/medicina58091204. PMID: 36143881; PMCID: PMC9503821.

7. Luu LA, Guffey DJ, Zlotoff BJ. Arthropathy and Cutaneous Eruption in a Patient With Cystic Fibrosis. JAMA Dermatol. 2019 Mar 1;155(3):375-376. doi: 10.1001/jamadermatol.2018.5018. PMID: 30673074.

8. Lampert S, Schahin SP, Wiest GH, Hahn EG, Ficker JH. Arthropathy and cutaneous manifestations in a 28-year-old patient with cystic fibrosis. Monaldi Arch Chest Dis. 2006 Jun;65(2):114-5. doi: 10.4081/monaldi.2006.575. PMID: 16913584.

9. Yonker LM, Marand A, Muldur S, Hopke A, Leung HM, De La Flor D, Park G, Pinsky H, Guthrie LB, Tearney GJ, Irimia D, Hurley BP. Neutrophil dysfunction in cystic fibrosis. J Cyst Fibros. 2021 Nov;20(6):1062-1071. doi: 10.1016/j.jcf.2021.01.012. Epub 2021 Feb 13. PMID: 33589340; PMCID: PMC8568301.

10. Smith, Edgar B., and Herman Beerman. "Sherlock Holmes and dermatology." International Journal of Dermatology 16.5 (1977).

11. Schidlow, D. V., et al. "Arthritis in cystic fibrosis." Archives of disease in childhood 59.4 (1984): 377-379.

12. Dixey, J. O. S. H., et al. "The arthropathy of cystic fibrosis." Annals of the rheumatic diseases 47.3 (1988): 218-223.