Abstract:

Cutaneousvasculitis encompasses cutaneous components of systemic vasculitides, skin-limited variants of systemic vasculitides, such as IgA vasculitis or cutaneous polyarteritis nodosa, and single-organ cutaneous vasculitis, as individualized in 2012 in the Chapel Hill Consensus Conference Nomenclature. In this article, we focus on the management of skin-limited and single- organ vasculitides, often referred to, in clinical practice, as isolated “cutaneous leukocyctoclastic vasculitis”, terms which may correspond to histological findings or descriptions, but are imprecise and not specific. Since most cases of isolated cutaneous vasculitis are self-limited and resolve spontaneously over 3 to 4 weeks, most patients require no systemic treatment. For those with severe, intractable, or chronic and recurring vasculitis, systemic therapy can be indicated and should be tailored to the severity of the disease. High-quality literature is lacking to guide management. Oral glucocorticoids may be required for a short period of time for painful, ulcerative, or otherwise severe disease in order to speed resolution. Among drugs which are reasonable longer-term options are colchicine, dapsone, azathioprine or hydroxychloroquine. Additional studies, including an ongoing multicenter randomized trial, are needed to determine the most effective therapies for skin-limited vasculitis.

Keywords: Vasculitis; cutaneousvasculitis; leucocytoclastic vasculitis; colchicine; dapsone;azathioprine

“Cutaneous vasculitis” is the generic term for various types of vasculitis affecting the skin, as defined by the Dermatologic Addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. [1] It encompasses cutaneous components of systemic vasculitis (e.g., cutaneous manifestations of eosinophilic granulomatosis with polyangiitis or hypocomplementic (anti-C1q) urticarial vasculitis syndrome), skin-limited or skin-predominate variants of systemic vasculitis (e.g., skin-limited IgA vasculitis or cutaneous polyarteritis nodosa [cPAN]), and single-organ types of cutaneousvasculitis that have no systemic counterparts. [2-7] This latter group was individualized only in 2012 in the Chapel Hill Consensus Conference Nomenclature, and includes nodular vasculitis (erythema induratum), IgM/IgG vasculitis, erythema elevatum et diutinum, hypergammaglobulinemic macular vasculitis, and normocomplementemic urticarialvasculitis. In this article, we will focus on the management of skin-limited and single-organ vasculitides, which were previously (and are still in clinical practice) often referred to as “cutaneous leukocyctoclastic vasculitis,” “leukocytoclastic vasculitis,” “hypersensitivity vasculitis,” and “cutaneous leukocytoclastic angiitis.” Whereas the latter terms may correspond to histological findings or descriptions, they are imprecise, and not specific.

1-Clinical presentation and diagnosis

Isolated or limited cutaneousvasculitis most commonly presents with palpable non-blanchable purpura on the lower extremities and other areas of dependency. It can be due to small- and/or medium-sized vessel vasculitides (as overlaps are common). The purpuric lesions result from the extravasation of erythrocytes through the inflamed and damaged blood vessel walls into the dermis. Petechiae or petechial purpura refer to smaller purpuric macules, although the clinical distinction maybe debatable, and may relate to smaller vessel involvement. Purpuric lesions are most commonly symmetrically distributed over the dependent regions of the body, especially the lower legs (Figure 1). The extent of cutaneous involvement is relevant to diagnostic considerations; when lesions are localized to a single site, it may suggest a secondary reaction to a local factor (e.g., trauma, arthropod bite).

The spectrum of cutaneous findings in patients can also include hemorrhagic vesicles or p53 immunohistochemistry bullae. In the most severe cases, the lesions can be necrotic, leading to painful ulcerations (Figure 2) or gangrene. Superinfection of open lesions is a risk. Urticarial lesions can also develop, although these are more classically seen in patients with urticarial vasculitis (often with anti-C1q antibodies measurable in the serum) or eosinophilic granulomatosis with polyangiitis. Patients with cutaneous vasculitis/arteritis involving medium-, rather than small-, sized vessels in the deep reticular dermis and subcutaneous tissue, may present with subcutaneous nodules, livedo reticularis, retiform purpura, or larger ulcerations.

Resolution of the skin lesions, spontaneously Oral Salmonella infection after a few weeks or months or under treatment,can leave behind post-inflammatory hyperpigmentation or scars.By definition, patients with skin-limited or skin-predominant vasculitis have no significant systemic manifestations. However, arthralgias of joints adjacent to skin lesions are common during and/or before the flares. The ankle is the most frequently affected joint due to the preference of immune complex-mediated vasculitis for the legs. Frank synovitis or arthritis is rare and suggests the presence of systemic disease. Some patients will have low-grade fever accompanying the clinical presentation. Patients with cutaneous IgA vasculitis may have some microscopic hematuria, with or without mild proteinuria, which does not impact treatment. If renal involvement is more advanced or progressive, with more significant hematuria and proteinuria and/or decreased glomerular filtration rate, the vasculitis should be considered to be systemic. Similarly, patients with cutaneous PAN can develop paresthesias in the vicinity of deep or ulcerative skin lesions due to damage to nearby cutaneous nerves; more significant neurological symptoms (e.g., mononeuritis multiplex) or symptoms outside the vicinity of skin lesions must be considered evidence of systemic vasculitis and treated as such.

The diagnosis of cutaneous vasculitis should be confirmed via skin biopsy. [4, 5, 8-11, 13, 14] Additionally, the presence of important underlying triggers and associated disease states which may affect prognosis and management should be carefully considered. Diagnostic investigations should be guided by the clinical history and examination. While no standard protocol for evaluation exists, a number of reviews provide more detailed recommendations and guidance regarding the appropriate work-up of patients presenting with skin lesions suspicious for vasculitis.[15-17] Age-appropriate malignancy screening may also be indicated depending on the context and associated clinical setting and preliminary results.

2-Disease patterns and outcomes

The overall prognosis of isolated or limited cutaneous vasculitis is usually favorable. The skin lesions often spontaneously regress within weeks or months, and there is no mandatory indication to treat every patient. The risk of progression from isolated, single organ, idiopathic cutaneousvasculitis to a systemic vasculitis is not fully understood but is felt to be low (<10% at 5 years).

However, some patients with acute episodes experience more significant pain, cutaneous necrosis, or ulceration, which may require treatment. In addition, approximately 10% of patients go on to develop a chronic and recurring disease course lasting longer than 4 weeks, characterized by continuous or waxing and waning crops of purpuric macules and papules.[17, 18] For such patients, systemic therapy is indicated to help address the associated discomfort,ulceration, and psychosocial impact.

In the event of refractory disease unresponsive to treatment, it is important to re-evaluate the diagnosis and consider further investigation for underlying etiologies, including
malignancy.Genetic mutations (e.g.adenosine deaminase 2 [ADA2] deficiency) have also been associated with refractory cutaneousvasculitic ulcers.[19, 20] Other pathogenic genetic variations will likely be discovered in the years to come.

3-Treatment of isolated or limited cutaneousvasculitis

Addressing or removing the inciting etiology, triggering agent, or medication may alone be therapeutically effective for those in whom one can be identified (approximately 50% of cases of cutaneous small vessel vasculitis are idiopathic). Some patients recognize factors which can precipitate a flare, such as prolonged sitting or standing, heat, exercise,alcohol consumption, or upper respiratory tract infections. Conservative measures, including rest and elevation and use of compression stockings, may help prevent immune complex deposition in the lower extremities and aid in wound healing. Topical steroids and moisturizers can help address pruritus and other local skin symptoms, though they do not prevent new lesions. Non-steroidal anti-inflammatory drugs may help address skin discomfort andarthralgias, when present.

Since most cases of isolated cutaneousvasculitis are self-limited and resolve spontaneously over 3 to 4 weeks,[18] most patients require no systemic treatment.[21] For those with severe, intractable, or chronic and recurring vasculitis, however, systemic therapy is indicated. Unfortunately, no robust body of literature is available to guide management, and therapeutic recommendations are based mostly on case reports, case series, and expert opinion.[11] Treatment should be tailored to the severity of the disease and its associated symptoms.

3.1-First-line therapy

Oral glucocorticoids (GC) may be required for painful, ulcerative, or otherwise severe disease in order to speed resolution. Initial doses of 0.5-1 mg/kg per day of prednisone are reasonable. No randomized trials have evaluated the use of systemic GC for isolated cutaneous vasculitis, but their efficacy has been reported in various case series and reviews.[17, 21, 22, 23] In most cases, they help prevent new lesion formation, and the dose can be tapered successfully over 3-6 weeks. It is important to note that while moderate-to-high doses of prednisone are usually effective in preventing new lesion formation,[24], they are not always. Regardless, systemic GC are not an advisable long-term strategy for chronic vasculitis, given their association with myriad treatment-related complications.[25-28] Patients with cutaneousvasculitis lasting longer than 4 weeks, as well as those who respond incompletely to GC or who are unable to taper them successfully without disease flare, should be given appropriate steroid-sparing agents.

Given the lack of high-quality literature to guide management, there is significant practice variation surrounding the choice of steroid-sparing agents. Among drugs which are reasonable first-line options are colchicine, dapsone, and azathioprine. These drugs are relatively safe and well-tolerated and, based on case reports and expert opinion, may be effective treatments for skin-limited vasculitis. In many patients, more than one drug must be tried before finding the most effective (and best-tolerated) drug. Other agents which can be considered, though with fewer case series or reports, include methotrexate, hydroxychloroquine, sulfasalazine,mycophenolate mofetil, leflunomide, and danazol.

Colchicine (typically 0.6 mg twice daily) has been reported to be useful for skin and joint symptoms in several open label case series.[21, 22, 29] The only randomized controlled trial for cutaneous small vessel vasculitis,a month-long study of colchicine in 20 patients, whose results were published in 1995, showed no significant benefit overall compared to placebo. However,some patients responded and later flared after discontinuation of the medication. [30] Gastrointestinal side effects, mainly abdominal discomfort or diarrhea, may be dose-limiting in some patients.

The use of dapsone at doses ranging from 50-200mg/day is supported by case reports and anecdotal experience.[31] The target dose for cutaneous vasculitis is usually 100-150mg/day. This therapy is often given alone but may also be combined with colchicine. Screening for glucose-6-phosphate dehydrogenase deficiency must be performed prior to initiation of the medication. Regular laboratory monitoring is needed to look for evidence of significant anemia; some degree of anemia is common even in the absence of overthemolysis. Methemoglobinemia is a rare, unpredictable side effect of dapsone.

Azathioprine is an immunosuppressive drug most often given at a dose of 2 mg/kg/day. Its successful use for cutaneousvasculitis has also been reported[22, 32], and it is used regularly in the treatment of various types of systemic vasculitis. Important potential adverse events include leukopenia (especially in patients with reduced thiopurine S-methyltransferase activity, who metabolize the drug more slowly), hepatic injury, hypersensitivity reaction, and infections.

An international multicenter study is ongoing to compare colchicine, dapsone, and azathioprine in patients with isolated skin vasculitis, including CSVV, skin-limited IgA vasculitis, and cPAN (ARAMIS; ClinicalTrials. gov Identifier: NCT02939573).[33] This is the second randomized study ever conducted in isolated skin vasculitis.

3.2-Severe or refractory disease

When cutaneous vasculitis is more severe or fails to respond to the above agents, alternative options should be considered. Depending on the severity of symptoms, more aggressive immunosuppressive drugs may be warranted. In the absence of any high quality data to guide management, however, patient comorbidities and the potential for toxicity should be considered.Methotrexate (15-25 mg/week) has been reported to be effective for the treatment of cutaneous vasculitis associated with autoimmune disease.[34] It has typically been considered part of the treatment ladder for cPAN[35, 36], particularly those with ulcerative disease, which is a marker for relapsing course and a need for more aggressive immunosuppression.[37] Mycophenolate mofetil (2-3 g/day) is another therapeutic option for patients with cutaneous small vessel vasculitis.[38] It may be particularly useful for patients with IgA vasculitis[39] or hypocomplementemic (anti-C1q antibody) urticarial vasculitis.[40] In rare instances, more aggressive therapies, including cyclosporine,[41] cyclophosphamide, infliximab,[42] rituximab,[43] or intravenous immune globulin [44] can be considered for severe and treatment-refractory disease. The risks of these agents must be carefully weighed against the extend of the cutaneousvasculitis and its symptoms.

3.3-Other therapies and special situations

Hydroxychloroquine (200 to 400 mg/day) has been utilized in some patients with success, primarily those with urticarial vasculitis, perhaps because of the frequent association of that disease with systemic lupus.[45] It is generally well-tolerated, though its potential ophthalmological toxicity is well known and requires regular monitoring.Pentoxifylline (typically 400mg three times daily) is a well-tolerated drug reported to be helpful for cutaneousvasculitis in combination with dapsone.[46, 47]

Multiple case reports and small case series support the use of dapsone for erythema elevatum diutinum.[48] Nodular vasculitis / erythema induratum associated with tuberculosis should be treated with anti-tuberculous combination therapy. Potassium iodide is considered an effective therapy for cases which are idiopathic or do not respond to treatment of an underlying trigger.[49, 50] Therapeutic options for other special types of single-organ cutaneousvasculitis are even more poorly-defined and draw mostly on the experience noted above with other types of cutaneousvasculitis.

3.4-Duration of therapy

The necessary duration of treatment for skin-limited vasculitis is unknown. It may take several weeks for a particular therapy to take effect. Once response has Caspase Inhibitor VI molecular weight been achieved, the decision to taper and ultimately discontinue therapy must be made on a case-by-case basis, depending on the severity of prior symptoms and the side effects of the therapy. In general, it is reasonable to consider tapering after cutaneousvasculitis has been in remission for 3-6 months, but there are no data to guide decision making.

4-Conclusion

While the prognosis of skin-limited vasculitis is generally favorable, the impact of painful, pruritic, or ulcerative skin lesions and chronic / recurring disease can be significant. With adearth of high- quality data to guide management, successful treatment can be elusive. The choice of therapy should balance the severity of symptoms against potential risks and patient comorbidities.Additional studies, including an ongoing multicenter randomized trial, are needed to determine the most effective therapies for skin-limited vasculitis.