Rituximab and dermatomyositis: Dr. Samitz would be proud

By Warren R. Heymann, MD
Nov. 20, 2019
Vol. 1, No. 37

The gifted dermatologist clinician-educator Morris H Samitz, MD, has been honored with an annual lectureship at the Perelman School of Medicine at the University of Pennsylvania for the past 44 years. Dr. Samitz passed away in 1993, but his legacy in medical dermatology remains with the “Samitz sign” of dermatomyositis (DM). The sign refers to “thickening, roughness, hyperkeratosis, and irregularity of the cuticle with minimal or no redness nor inflammation.” Dr. Samitz described six such cases; in an additional two cases of cuticular fraying (examined with the late dermatologic luminary Dr. Stefania Jablonska in her department in Warsaw) capillaroscopic studies also demonstrated classical nailfold features of dermatomyositis (large, tortuous capillaries accompanied by an overall decreased capillary density). (1)

DM is an autoimmune idiopathic inflammatory disease affecting both skin and muscle. Classic dermatological manifestations include the facial heliotrope rash, the neck shawl sign, and erythematous, lichenoid Gottron papules over the dorsum of the hands. In addition to the Samitz sign, other characteristic features of DM include poikiloderma in photosensitive areas, a malar as well as a violaceous erythema on the extensor surfaces, and a diffuse, erythematous, scaling, and non-scarring alopecia. Patients with adult-onset DM have an approximately 15% risk of an associated malignancy. Interstitial lung disease is associated, being linked to those with ant-Jo-1, anti-MDA-5, and anti-CADM-140 antibodies. Patients with juvenile DM are at risk for calcinosis cutis. Patients displaying skin manifestations only are diagnosed with amyopathic DM; those with muscle disease, but clinically asymptomatic, are diagnosed as hypomyopathic DM. Treatment for DM focuses on corticosteroids and other immunosuppressive agents (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, IVIG, cyclophosphamide). Of the biologics, there has been increasing data favoring the use of rituximab. (2)

The initial report of rituximab for the treatment for DM was in 2005. Levine assessed 6 DM patients in an open-label pilot study and found maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab. CD20+ B cells were effectively depleted in all patients by 12 weeks. Four patients experienced a return of symptoms that coincided with the return of B cells before the 52-week end point. Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells. Other symptoms of DM, including rash, alopecia, and reduced lung forced vital capacity, improved markedly in patients with these symptoms. Rituximab was well tolerated, with no treatment-related severe or serious adverse events observed. (3)

There has been ample literature to support the use of rituximab for recalcitrant cases of DM. Aggarwal et al performed a randomized placebo-phase-controlled trial on patients with refractory adult DM (n = 72) and juvenile DM (n = 48). Patients were treated with rituximab either early (week 0/1) or late, (week 8/9), so that all received rituximab. Stable concomitant therapy was allowed. There were statistically significant improvement in cutaneous disease activity from baseline to the end of the trial after rituximab administration in both adult DM and juvenile DM subsets, with a trend for faster cutaneous response in the early group (20% relative improvement from baseline) compared with those receiving B cell depletion later. (4)

Miossi et al evaluated 23 DM patients with < 12 months of symptoms utilizing nailfold capillaroscopy (NC). Significantly higher serum angiogenin (ANG) and vascular endothelial growth factor-1 (VEGF1) levels were observed in DM patients than in controls. Capillary density and avascular areas correlated positively and negatively, respectively, with serum levels of ANG. Additionally, the capillary density correlated inversely with the number of enlarged and giant capillaries and avascular areas. The number of enlarged capillaries correlated positively with the presence of a facial rash, giant capillaries, and microhemorrhages. VEGF1 showed no relationship with the NC parameters with DM-related clinical and laboratory features. Additionally, 15 out of 23 patients were assessed prospectively after 3.21 years. All patients had a major clinical response with significant improvement in all NC parameters, except for enlarged and bushy capillaries. The authors concluded that nailfold capillaroscopy may be a useful in assessing disease activity in recent-onset DM, and also implicating the role of ANG in the angiogenesis observed in DM. (5) Argobi and Smith, studying 45 DM with NC found that 80% of rituximab treated patients had normal nailfold capillaries at 6 month follow-up and 100% at 2 years. Patients treated with other immunosuppressive agents had no alterations in their nailfold capillary patterns after 2 years. The authors suggested that rituximab’s unique effect on the microvasculature could propel rituximab to first-line therapy for DM. (6)

How does rituximab, a monoclonal antibody that depletes CD20+ cells, treat microangiopathy? The answer may lie in its efficacy for a rare disease — isolated pauciimmune pulmonary capillaritis (IPPC). IPPC presents as diffuse alveolar hemorrhage due to underlying pulmonary capillaritis, but without clinical or serologic findings of an associated underlying systemic disorder. (7) Presumably, rituximab’s reduction in the number of activated B cells, decline in the levels of B-lymphocyte stimulator factors including B-cell activating factor, and secondary effects on T-cell function, may influence endothelial function.

Steven R. Cohen, MD, MPH, chief of the division of dermatology at the Albert Einstein College of Medicine and Dr. Samitz’s son-in-law, stated that Dr. Samitz imparted the wisdom of pragmatism by the following credo — “learn from your teachers, learn from your patients, and always trust your intuition.” (8) My intuition is that unraveling rituximab’s precise role on microvascular pathology is worthy of continued research.

Our Expert’s Viewpoint

Steven R. Cohen, MD, MPH
Chief, Division of Dermatology
Albert Einstein College of Medicine

Beyond the putative effect on endothelial function in dermatomyositis, there may be other targets associated with depleting CD20+ lymphocytes suggested by an increasing range of primary and secondary skin disorders treated with rituximab, including pemphigus vulgaris, cicatricial pemphigoid, bullous pemphigoid, pretibial myxedema, and antiphospholipid syndrome.

I am currently using rituximab in a patient with severe thyroid dermopathy (pretibial myxedema) that was misdiagnosed as elephantiasis nostros verrucosa.

I am touched and honored by this association with Dr. Samitz. Of all my great teachers (and I have had some great teachers, including Marty Carter, Irwin Braverman, Aaron Lerner, and George Hambrick to name a few), Dr. Samitz continues to inform my consciousness with every patient I see. That quote in Dr. Heymann’s commentary celebrates the rare nexus of science and humanity.

1. Samitz MH. Cuticular ch anges in dermatomyositis: A clinical sign. Arch Dermatol 1974; 110: 866-867.

2. Isak V, Jorizzo JL. J Dermatolog Treat 2018; 29: 450-459.

3. Levine TD. Rituximab in the treatment of dermatomyositis. Arthritis Rheum 2005; 52: 601-607.

4. Aggarwal R, Loganathan P, Koontz D, Qi Z, et al. Cutaneous improvement in refractory adult and juvenile dermatomyositis after treatment with rituximab. Rheumatology (Oxford) 2017; 56: 247-254.

5. Miossi R, de Souza FHC, Shinjo SK. Nailfold capillary changes in adult new-onset dermatomyositis: A prospective cross-sectional study. Clin Rheumatol 2019; Apr 23. doi: 10.1007/s10067-019-04537-x. [Epub ahead of print]

6. Argobi Y, Smith GP. Tracking changes in nailfold capillaries during dermatomyositis treatment. J Am Acad Dermatol 2019; 81: 275-276.

7. Thompson G, Specks U, Cartin-Ceba R. Isolated pauciimmune pulmonary capillaritis successfully treated with rituximab. Chest 2015; 147: e134-e136.

8. Cohen, SR. Teachings of a lifetime. Directions in Residency, AAD. Summer 2010.