Scleroderma, Vasculitis & Myositis Center

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Two studies recently reported in the New England Journal of Medicine offered hope for patients with idiopathic pulmonary fibrosis (IPF). In a phase III trial of Pirfenidone, an oral anti-fibrotic therapy, patients treated with Pirfenidone demonstrated less disease progression as measured by lung function and exercise tolerance, as well as improved progression free survival compared with patients treated with placebo.

Similarly, a study looking at the efficacy of nintedanib, an oral tyrosine kinase inhibitor, similarly demonstrated that patients with IPF treated with active medication showed less progression of disease compared to those treated with placebo. Other trials of tyrosine kinase inhibitors in systemic sclerosis including some performed at Hospital for Special Surgery in the Scleroderma, Vasculitis & Myositis Center have suggested that this class of medications may potentially have a role in scleroderma. The phenotypic and pathologic similarities between systemic sclerosis associated interstitial lung disease (ILD) and IPF suggest that these agents may be of relevance in scleroderma ILD, and perhaps in scleroderma in general.

King Jr, Talmadge E., et al. "A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis." New England Journal of Medicine (2014).
Richeldi, Luca, et al. "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis." New England Journal of Medicine (2014).


Polyarteritis Nodosa (PAN)

Polyarteritis Nodosa (PAN) is a systemic vasculitis affecting medium-sized muscular arteries; organ systems commonly involved in PAN include the skin, nervous system, gastrointestinal tract and kidneys. While development of PAN has been associated with certain infections (such as hepatitis B) or malignancies (hairy cell leukemia), the cause of the vast majority of PAN is unknown. Two articles recently published concurrently in the New England Journal of Medicine report the discovery of a genetic mutation leading to a PAN-like vascular disease.

Using genome sequencing technology, both these groups found the same single gene was mutated in all the patients studied who had either familial or childhood-onset PAN. This mutation, in the gene encoding Adenosine Deaminase 2 (ADA2), leads to a loss-of-function in ADA2. The PAN clinical phenotype was highly variable in patients with the ADA2 deficiency ranging from isolated cutaneous involvement with livedo reticularis to a phenotype of early onset lacunar strokes associated with fevers and wide-spread vasculopathy, suggesting modifying environmental or additional genetic factors influence clinical presentation. Decreased ADA2 enzymatic function was demonstrated from serum samples of affected individuals and in an animal model, replacement of ADA2 ameliorated the disease phenotype. ADA2 is known to play a role in purine metabolism as the main extracellular adenosine deaminase. ADA2 is also growth factor for endothelial cells and leukocytes and is implicated in macrophage proliferation. The mechanism by which ADA2 deficiency causes the clinical phenotype of PAN vasculopathy is not yet elucidated. Nonetheless, this discovery that a single gene defect results in a variant of PAN will hopefully provide insight into disease pathogenesis.

In the future, genetic testing in certain high risk populations may aid the diagnosis of familial PAN and therapies to replace deficient ADA2 may be used to treat PAN patients with this mutation.

Zhou Q, Yang D, Ombrello AK et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911-20.
Navon Elkan P, Pierce SB, Segel R et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921-31.

Granulomatosis with Polyangiitis (Wegener's)

As one of the antineutrophil cytoplasmic antibody (ANCA) associated vasculitides, Granulomatosis with Polyangiitis (GPA) is a multisystem disease characterized by small to medium vessel necrotizing vasculitis with granulomatous inflammation. GPA has a predilection for the respiratory epithelium of both the upper and lower airways and the kidneys. Otolaryngologic (ENT) manifestations, including rhinosinusitis, serous otitis media and subglottic inflammation, are the most prevalent manifestations of GPA and are present in greater than 90% of patients. Damage in the ENT domain is also frequent. ENT disease activity and damage is also a major determinant of quality of life in patients with GPA. While rituximab is an accepted therapy for severe vasculitic manifestations of GPA, the use of rituximab for the granulomatous ENT manifestations, which are a hallmark of GPA, is debated.

Recently, the largest experience of rituximab for ENT manifestations of GPA was published in Arthritis Care and Research. Using a decade of well-characterized retrospective data from >900 office visits, the investigators were able to identify 51 patients with active ENT disease who received rituximab and compare them to 49 GPA patients with active ENT disease who were receiving other therapies. The authors found that patients receiving rituximab were 11 times less likely to have active ENT disease compared to patients being treated with any other therapy (including methotrexate, azathioprine, cyclophosphamide and trimethoprim-sulfamethoxazole). Steroid doses were comparable in those receiving rituximab and those on other therapy. The strength of the relationship between rituximab and ENT remission remained after adjusting for relevant clinical factors such as disease severity or duration. The results of this retrospective study strongly support the effectiveness of rituximab for ENT disease in GPA, though prospective controlled studies are needed.

Lally L, Lebovics RS, Huang-WT, Spiera RF. Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangitiitis. Arthritis Care Res 2014;66(9)1403-9

Rheumatology Narrative Medicine Journal, the First Exclusively Devoted to Rheumatology

Rheum to Grow: Stories of Health and Humanity at Hospital for Special Surgery (Calling for Submissions)
This is a journal for, by and about our patients and their caregivers. We welcome poetry, photography or prose, on or related to themes of health, healing, navigating illness, mind, body and/or self-transformations within the field of rheumatology. We will accept pieces from patients with arthritis, autoimmune diseases, pain disorders affecting joints, and osteoporosis. Relevant book reviews, commentaries and opinion pieces, and contributions on or related to ethics, public health/health policy or careers in rheumatology are all welcome. We are eager for pieces from patients who have something to say about medicine, rheumatology in particular, and health professionals, practicing or retired. Learn more about how to submit.

Challenge Grant

Hospital for Special Surgery's Scleroderma, Vasculitis, & Myositis Center has received a challenge grant from an anonymous donor to match every dollar donated to the Center's Rudolph Rupert Scleroderma Research Program, up to $50,000.Your support will fund critical scleroderma research, as well as community outreach and patient and physician education.Learn more about how to leverage your gift and help fight scleroderma.