There are very limited data on topical immune modulators (which have indications for psoriasis and atopic dermatitis), and their expected benefit for patients with deep dermal disease is low, but they do offer the benefit of being inexpensive and generally low-risk. In a case series of 18 patients with cGVHD, 13 of the 18 found a benefit from topical tacrolimus in terms of scaling, pain, or “tightness,” but validated response scales were not used and the patients did not necessarily have the sclerotic disease [17]. For patients with superficial dermal disease (ie, lichen sclerosus–like disease) topical corticosteroids and calcineurin inhibitors may have a particular benefit. Topical corticosteroids and calcineurin inhibitors are the standard of care for patients with lichen sclerosus. A typical treatment consists of a super-high-potency corticosteroid such as augmented betamethasone dipropionate 0.05 % or clobetasol 0.05 % cream/ointment applied twice daily to the affected area, then transitioning to tacrolimus 0.1 % ointment as the patient improves. The transition to tacrolimus ointment is important, to prevent concerns such as worsening of dermal atrophy, telangiectasias, and development of striae. One should be wary of occluding the tacrolimus ointment for long periods of time or over large surface areas, as systemic absorption has occurred in patients with cGVHD. Using lichen sclerosus as a model, it appears very reasonable to treat patients with superficial cutaneous cGVHD initially with topical immunomodulators. For patients with deeper disease, one can try to use topical immunomodulator to manage the associated pruritus.

Based on the action spectrum of available phototherapy wavelengths, ultraviolet A (UVA) spectrum with the longer wavelengths (320–400 nm) would appear more effective for deeper disease. To maximize the strength of the UVA and minimize the amount of required time for patients, patients may ingest 8-methoxypsoralen (psoralen + UVA = PUVA or photochemotherapy) or have the same compounded into a 1 % topical ointment to be applied 30–60 min prior to the phototherapy. The other commonly used light spectrum is narrow-band ultraviolet B (nbUVB, 311–313 nm). The advantage of this wavelength is that it is shorter, with a decreased risk of melanoma and nonmelanoma skin cancers. With the shorter wavelength, however, it is generally considered less able to treat deep skin disease. Both treatments work through inactivation of antigen-presenting cells and activated T cells, while building antigen tolerance over time. One side benefit from instituting phototherapy is the reduction in itch, although it generally takes about 2 months for improvement. A systematic review has suggested a benefit from both UVA1 and PUVA for patients being treated for sclerotic-type cGVHD as well as for the prototype diseases—lichen sclerosus, morphea, and eosinophilic fasciitis [18].

High-dose (1 mg/kg) oral corticosteroids and steroid-sparing agents such as mycophenolate mofetil make up the first-line standard of care for patients with moderate or severe cGVHD. If patients improve, then the corticosteroids are weaned. In practice, if the patient’s GVHD is skin-predominant, utilizing a skin-directed therapy such as PUVA or UVA1 or an immunomodulator such as extracorporeal photopheresis (ECP) is a reasonable option to help wean systemic corticosteroids. If steroids fail, there is no clear evidence-based escalation. Although steroid-sparing options such as mycophenolate mofetil and cyclosporine are available, studies have shown no treatment benefit for the latter [26] and actually decreased survival for the former [27].

Tacrolimus tends to be the default immunosuppression after transplantation. Its dose is titrated to effect based on whether acute or overlap GVHD develops, but there are reports that sirolimus may be an effective additive. In the initial paper, 8 of 11 patients with sclerotic involvement of their skin responded to therapy with low-therapeutic dosing of sirolimus in combination with their typical immunosuppression [28]. Similarly, in follow-up studies, 70–94 % of patients with sclerotic cGVHD demonstrated some improvement with immunosuppressant regimens inclusive of sirolimus [29, 30]. However, drug interactions, acute kidney injury, and edema may limit its use [31].

In patients with severe cGVHD, including 20 with extensive cutaneous lichenoid or sclerotic involvement, a 53 % improvement in scoring measurements was seen, and over 80 % of patients were able to decrease their concomitant immunosuppression [32]. Patients with sclerotic-type cGVHD actually may have a slightly higher response rate to ECP (71 %) when compared with all patients with cutaneous cGVHD (59 %) [33]. In a prospective study, patients were able to decrease their standard immunosuppression and showed significant skin improvement in the nonblinded analysis [34].

There is also evidence for the use of rituximab, a monoclonal CD20 chimeric antibody typically reserved for lymphomas, leukemias, rheumatoid arthritis, and autoimmune blistering diseases. It is dosed in the lymphoma protocol, at 375 mg/m² × 4 weeks, a regimen that can be repeated after 3 months. In early studies of eight patients with sclerotic-type cGVHD, clinical improvement was noted in four, including improvement in pulmonary function testing from loosening of the chest wall [35]. Further prospective studies on cutaneous sclerosis have demonstrated a significant clinical response in 27 % of patients, no higher than patients treated with imatinib [36]. Of note, the study used different validated scoring methods than most cGVHD studies. A meta-analysis of rituximab in this setting asserted that cutaneous response rates vary between 0 % and 83 %, but small study sizes and variable outcome measures prevent clear interpretation [37].

Imatinib, a tyrosine kinase inhibitor targeted to the Philadelphia chromosome, has shown abilities to modulate transforming growth factor–β and platelet-derived growth factor. It is typically dosed at 400 mg daily in adults. Although it demonstrated substantial cutaneous improvement in several early case series, it demonstrated only 30–35 % partial response in larger case series of patients with sclerotic-type cGVHD [38, 39]. When compared prospectively with rituximab, the rate of a significant clinical response in the skin was only 26 % [36].

Ruxolitinib, a selective JAK1/JAK2 inhibitor approved for use in myelofibrosis and polycythemia vera, has recently become a new agent for cGVHD treatment. Overall, the data are sparse. An early preclinical study [40] led to a prospective trial demonstrating an 85 % overall response rate [41], but the response rate differed from rates in previous studies and was based on the ability to taper steroids and systemic immunosuppression by 50 %. No clear specifics were given on the form of cutaneous cGVHD treated.