A single case report has the potential to change the world: Could JAK inhibition alter the trajectory of multicentric reticulohistiocytosis?

By Warren R. Heymann, MD, FAAD
July 20, 2022
Vol. 4, No. 29

One of the joys of practicing in the Delaware Valley is participating in the Philadelphia Dermatological Society (PDS). The local institutions each provide superlative patient presentations and lectures — the range of case presentations is stunning. For many patients (in the pre-COVID era when live patients were examined, and hopefully again post-COVID), it provides an opportunity for them to share their story and perspective, while providing hope that someone — anyone — might offer a therapeutic idea to help them.

Although the overwhelming majority of patients presented by each program are new to the PDS every year, there was one particular patient (I will call her Mary Ruth) who participated in the Jefferson meeting several times. She was a wheel-chair-bound middle-aged woman with a radiant smile and charm who wanted every observer, from medical student to senior attending dermatologist, to witness the thousands of reticulohistiocytomas riddling her skin, and her crippling arthritis mutilans. Her generosity of spirit and resilience in the throes of her devasting multicentric reticulohistiocytosis (MR) compelled the desire to offer help. I do not know her current status, but help may now be forthcoming for patents profoundly affected by MR.

MR is a rare (approximately 300 reported cases), non-Langerhans cell histiocytosis, characterized by red-brown papulonodular cutaneous lesions and destructive arthritis. It is more likely to affect women (female:male ratio of 3:1) and is usually diagnosed between the patient’s fourth and fifth decade of life. The papulonodules can be scattered or grouped and are usually distributed on the face, hands, and juxta‐articular areas. MR can also present with mucosal lesions in up to half of all cases. The papules are classically found periungually (so-called “coral beads”) and in the nasolabial folds. (1,2) There have been multiple reports of MR mimicking dermatomyositis, however, skin biopsies demonstrate reticulohistiocytomas. Histologically, the histiocytes have a “ground glass” appearance, staining positive for CD68, CD163, and HAM56 but negatively for S100, CD1a, and CD207 (Langerin). (3) Interestingly, approximately 15% of cases of MR have a coexisting autoimmune or connective tissue disease such as systemic lupus erythematosus, Sjögren syndrome, or scleroderma. (2)

Up to 30% of patients with MR may have an associated malignancy, thereby being classified as a paraneoplastic disorder by some authors. Primary cancers of the lung, breast, skin, thymus, gynecologic organs, gastrointestinal tract, and leukemia have been reported. The arthritis is described as symmetric and erosive, typically affecting the fingers, hands, wrists, and knees. Progression to arthritis mutilans may be observed in about 45% of patients. (3)

The largest series of patients with MR was reported by Sanchez-Alvarez et al. The authors identified 24 patients with biopsy-proven MRH (58% female, 75% Caucasian, median age at diagnosis 52 years, median follow-up of 2.3 years). All patients had cutaneous and articular involvement; 23 (96%) patients had papulonodular skin lesions (87% periungual and dorsal hand) and seven (30%) mucosal nodules; and 22 (92%) patients had arthralgias, 21 (88%) joint effusions, and 13 (54%) synovitis. Most frequently used therapies included corticosteroids, cyclophosphamide, methotrexate and bisphosphonates. Biologics (etanercept, adalimumab, infliximab) were used in four patients). Nine patients had symptomatic resolution at 1 year and 12 demonstrated partial improvement. Radiological findings included erosive changes in three (60%) patients and arthritis mutilans in two patients (40%). Twenty-nine percent of patients had a concomitant autoimmune disease and 25% had a malignancy, including melanoma, endometrial, peritoneal and lung carcinoma. The 5-year survival rate was 85%. (4)

The etiology of MR is an enigma, although some have hypothesized a relationship to the activation of histiocytic receptor activator of nuclear factor kappa-B ligand (RANKL) on the skin and joints. A precise understanding of MR’s pathophysiology should lead to targeted therapies in the future.

In the interim, we utilize steroids and DMARDs as first-line therapy, hoping for the best. I am old enough (and hopefully wise enough) by now not to get overexcited by single case reports, but in the case of MR presented by Niaki et al, I will make an exception. The authors detail the case of 50+ year-old woman with severe biopsy-proven MR accompanied by joint symptoms and a remote history of breast and ovarian cancer. Unresponsive to standard therapies, upadacitinib (Rinvoq) was prescribed — she experienced substantial improvement within 8 weeks, with nearly complete resolution of her skin lesions, and 75% improvement of arthritis, after 5 months of therapy. (5) I encourage you to review the dramatic before and after photographs. Upadacitinib is a JAK1 selective inhibitor that was approved by the FDA in 2019, indicated for patients with rheumatoid arthritis with inadequate responses or intolerance to one or more DMARD, either as monotherapy or in combination with methotrexate. (6)

It is bittersweet to see advances in medical therapy and think of those who could have benefitted from these discoveries. I would wager that Mary Ruth would have been thrilled that there is now hope for those afflicted with this ravaging disease. Even a single case report can change their world.

Point to Remember: Multicentric reticulohistiocytosis can devastate lives from its effect on the skin and joints. Further research on the use of JAK inhibitors is warranted as a therapeutic alternative.

Our expert’s viewpoint

Jason B. Lee, MD, FAAD
Clinical Vice Chair
Director, Jefferson Dermatopathology Center
Director, Jefferson Pigmented Lesion Clinic
Jefferson University Hospitals

I remember well the patient mentioned in this article by Dr. Heymann. She is one of those patients from whom we learn more than from any books, lectures, and our teachers. She taught me not only about the devastating nature of the rare disease but also about the remarkable resilience of the human spirit — the capacity of human courage, perseverance, and endurance in the face of a devastating and crippling disease. At the age of 13, much earlier than the average age of onset, our patient started to develop numerous skin lesions and severe arthritis that left her wheelchair-bound early in her adulthood. (7) Despite her severely disfiguring, debilitating disease that has ravaged her body, she did not let the condition affect her spiritual and emotional side of her as she was predictably confident, animated, and cheerful, frequently speaking in jest during my encounters with her.

The dramatic clinical improvement with upadacitinib, a Janus kinase (JAK) 1inhibitor approved for rheumatoid arthritis, observed by Niaki and co-workers, provides hope for all those suffering from the debilitating and crippling sequelae of MRH. Unfortunately, our patient did not live long enough to benefit from the advances in JAK inhibition therapies as she succumbed to her disease and prematurely died at the age of 45 in 2009.

We are in the midst of a nascent golden age in the treatment of dermatologic immune and non-immune mediated inflammatory diseases with JAK inhibitors. While rheumatologists have been using tofacitinib since 2012 when it was first approved for rheumatoid arthritis, dermatologists, a decade later, now have access to several newly FDA approved JAK inhibitors, namely, two oral agents upadacitinib (Rinvoq) and abrocitinib (Cibinqo), and topical ruxolitinib (Opzeulra) for atopic dermatitis. A slew of clinical trials and studies are underway investigating the efficacy of JAK inhibitors in the treatment of a variety of inflammatory skin diseases that include alopecia areata, inflammatory diseases, lichen planopilaris, hidradenitis suppurativa, alopecia areata, sarcoidosis, dermatomyositis, and systemic lupus erythematosus, taking advantage of the fact that Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is involved in the pathogenesis of these diseases. (8,9)

Advances in JAK/STAT signaling pathway inhibition have unlocked the potential to improve dramatically the lives of those who are afflicted by chronic dermatologic inflammatory diseases, many of which have devastating sequelae if left untreated. I am confident that the emerging JAK inhibitors will alter the trajectory of many of these chronic diseases. I now wonder how the trajectory of our patient would have changed had she been the beneficiary of early intervention with JAK/STAT signaling pathway inhibition.

1. Kantardjiev V, Beshanska-Pedersen B, Obreshkova E. Reddish-brown papules and nodules on the hands. JAAD Case Rep. 2020 Dec 25;9:18-20. doi: 10.1016/j.jdcr.2020.12.020. PMID: 33598519; PMCID: PMC7868736.

2. Kim S, Khatchaturian EM, Dehesa L. Multicentric reticulohistiocytosis: A case report with response to adalimumab. Clin Case Rep. 2020 Jun 22;8(8):1560-1563. doi: 10.1002/ccr3.2926. PMID: 32884795; PMCID: PMC7455448.

3. Fronek L, Bindernagel R, Segars K, Miller R. Multicentric reticulohistiocytosis masquerading as cutaneous connective tissue disease. Dermatol Online J. 2021 Mar 15;27(3):13030/qt37h8p3rp. PMID: 33865276.

4. Sanchez-Alvarez C, Sandhu AS, Crowson CS, Wetter DA, McKenzie GA, Lehman JS, Makol A. Multicentric reticulohistiocytosis: the Mayo Clinic experience (1980-2017). Rheumatology (Oxford). 2020 Aug 1;59(8):1898-1905. doi: 10.1093/rheumatology/kez555. PMID: 31742640.

5. Niaki OZ, Penn E, Scott DA, Cobos G, Vleugels RA, Weinblatt ME. Treatment of Severe Multicentric Reticulohistiocytosis With Upadacitinib. JAMA Dermatol. 2021 Jun 1;157(6):735-737. doi: 10.1001/jamadermatol.2021.0996. PMID: 33950153.

6. Kim HO. Development of JAK inhibitors for the treatment of immune-mediated diseases: kinase-targeted inhibitors and pseudokinase-targeted inhibitors. Arch Pharm Res. 2020 Nov;43(11):1173-1186. doi: 10.1007/s12272-020-01282-7. Epub 2020 Nov 8. PMID: 33161563.

7. Hsu S, Ward SB, Le EH, Lee JB. Multicentric reticulohistiocytosis with neurofibroma-like nodules. J Am Acad Dermatol. 2001;44(2 Suppl):373-375. doi:10.1067/mjd.2001.107779

8. Chapman S, Kwa M, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part I. A comprehensive review. J Am Acad Dermatol. 2022;86(2):406-413. doi:10.1016/j.jaad.2021.07.002

9. Chapman S, Gold LS, Lim HW. Janus kinase inhibitors in dermatology: Part II. A comprehensive review. J Am Acad Dermatol. 2022;86(2):414-422. doi:10.1016/j.jaad.2021.06.873

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