New Guidance on Managing Sjögren's Rheumatologic Problems

Janis C. Kelly

August 02, 2016

The first US clinical practice guidelines for management of primary Sjögren's system were published online July 7 in Arthritis Care & Research and include a decision tree for the use of oral disease-modifying antirheumatic drugs (DMARDs) for inflammatory musculoskeletal (MSK) pain, guidance on patient self-care and exercise to reduce fatigue, and recommendations for uses of rituximab in Sjögren's. The Clinical Practice Guidelines Committee discouraged the use of tumor necrosis factor-α (TNFα) inhibitors for patients with Sjögren's who lack other indications for those agents, including patients with sicca symptoms.

Lead author Steven E. Carsons, MD, chief, Division of Rheumatology, Allergy and Immunology, Winthrop-University Hospital Campus, and professor of medicine, Stony Brook University School of Medicine, Mineola, New York, told Medscape Medical News, "This is the first set of published clinical practice guidelines designed for US clinicians. The Sjögren's Syndrome Foundation's directors and clinical leadership has long recognized the need for guidance in the management of this complex disorder that spans multiple specialties and has few established, effective therapies."

The key points for clinicians are not to neglect simple nonpharmacologic approaches (such as exercise for patients with fatigue associated with primary Sjögren's), to begin pharmacologic therapy with the drugs having the lowest potential for adverse effects and escalate therapy according to response, and to prescribe biologic agents only for carefully selected patients, Dr Carsons explained. "These guidelines should provide a more uniform approach to selecting therapies for patients with Sjögren's, particularly DMARDs and/or biologic agents," he said.

DMARDs for Inflammatory Musculoskeletal Pain

Eric L. Matteson, MD, chair of rheumatology at the Mayo Clinic, Rochester, Minnesota, who was not involved in developing the guidelines, told Medscape Medical News, "I think this is a helpful step in the right direction and will be helpful to practicing clinicians and their patients. There is lots of uncertainty surrounding both the diagnosis and the management of Sjögrens syndrome. A major point will be that there is a role for DMARDs including rituximab for managing serious organ involvement in Sjögrens syndrome. A second point is, as the authors acknowledge, that highest-quality evidence is lacking for evaluation of the role of DMARDs and biologics in the management of fatigue and sicca complex (dry eyes and mouth), although there is some evidence some of these measures may be helpful for these problems."

Hydroxychloroquine (HCQ) "remains the first line therapy for inflammatory musculoskeletal pain in Sjögren's," but the reviewers also considered scenarios in which HCQ-responsive patients must discontinue the drug because of toxicity, because HCQ produces inadequate response, because patients with severe steroid-responsive pain need another DMARD for steroid-sparing, or because patients have evidence of synovitis.

The guideline provides a decision-tree table beginning with HCQ and progressing to methotrexate (MTX), then HCQ plus MTX, then short-term corticosteroids, then long-term (>1 month) corticosteroids.

Biologic Therapies in Primary Sjögren's

The panel recommended that clinicians not use TNFα inhibitors to treat sicca symptoms in patients with primary Sjögren's, but consider them in patients who also have rheumatoid arthritis (RA) or related conditions. The authors also note there is "no evidence that the subset of RA patients with Sjögren's who have been treated with anti-TNF-α agents have an increased incidence of lymphoma. Therefore, this recommendation should not be interpreted to discourage use of TNF inhibitors in situations where there is overlap with RA or where TNFα inhibition therapy is indicated for the treatment of inflammatory arthritis."

The group recommended that clinicians consider rituximab for treating keratoconjunctivitis sicca in patients with primary Sjögren's inadequately controlled by conventional therapies including topical moisturizers, secretagogues, anti-inflammatory agents, immunomodulators, and punctual occlusion. They also recommended consideration of rituximab for xerostomia in patients with primary Sjögren's who have some residual salivary production and significant evidence of oral damage inadequately controlled by conventional therapies, including topical moisturizers and secretagogues.

The authors also recommend rituximab as a possible option for adults with primary Sjögren's and a variety of other systemic manifestations including vasculitis with or without cryoglobulinemia, severe parotid swelling, inflammatory arthritis, pulmonary disease, or peripheral neuropathy (especially mononeuritis multiplex).

The authors caution that patients receiving rituximab should be monitored closely for toxicity.

Dr Matteson commented, "I think this is a very reasonable conclusion based on the available evidence."

The Problem of Fatigue in Primary Sjögren's Syndrome

One change made as a result of this process in the draft guideline recommendation on fatigue was in relation to the use of HCQ.

Dr Carsons said, "The original version reflected results of a well done but relatively small (122 subjects) randomized study of HCQ in Sjögren's performed in Europe. This study showed no benefit of HCQ for fatigue; thus, the initial draft version of this guideline stated that HCQ should not be used for treatment of fatigue in Sjögren's. As this would have had the effect of totally eliminating HCQ as a possible option, the consensus expert panel did not agree, and their vote did not reach the 75% level of agreement necessary for approval. Using this feedback, the guideline wording was modified to: HCQ may be considered in selected situations to treat fatigue in Sjögren's. The wording change resulted in a second-round vote to approve the modified recommendation. This outcome reflects the vast clinical experience of the expert panel and also underscores the need for further studies of HCQ, particularly in the US population."

The guidelines do not recommend DHEA, etanercept, or infliximab for treatment of fatigue in Sjögren's and note that there are not enough data or clinical experience to make a recommendation on use of anakinra, abatacept, belimumab, or epratuzumab for fatigue.

Dr Carsons said, "The process brought to light several preliminary studies highlighting emerging biologic therapies for Sjögren's. Although these studies were too preliminary to qualify for data extraction and guideline development, they raised important questions regarding the future role of biologics in Sjögren's management."

How the Sjögrens' Guidelines Were Developed

Dr Carson and colleagues first developed clinical management questions for the systemic manifestations of Sjögren's, guided by the 13-member Clinical Practice Guidelines Committee with input from patients and rheumatologists. The process was funded and conferences staffed by the Sjögren's Syndrome Foundation, with additional guidance from the American College of Rheumatology Quality of Care committee and staff members. There were working groups on rheumatology/systemic disease, ocular, and oral manifestations of primary Sjögren's (without a second major rheumatic/autoimmune disease). The current report was from the rheumatology/systemic disease working group.

The panel initially identified 97 potential topics for guideline development, which they narrowed to 16, all expressed as clinical questions. The authors write, "This manuscript reports on the following three questions: 1) Are nonbiologic DMARDs...useful for the treatment of inflammatory...MSK...pain; 2) Are biologics effective and safe in management of sicca and systemic manifestations; and 3) Are there effective management strategies for fatigue?"

Each of these questions was then assigned to a topic review group (TRG) with expertise in that area. This included three rheumatologists on the "Musculoskeletal TRG"; two rheumatologists, two oral medicine specialists, and an ophthalmologist on the "Biologic TRG"; and three rheumatologists on the "Fatigue TRG."

Each TRG performed systematic reviews, extracted data, and drafted guidelines, which were rated for quality of evidence and strength of recommendation.

Dr Carsons said, "We were pleasantly surprised at the rapidly growing number of publications on Sjögren's in the rheumatologic literature, as evidenced by the literature search diagrams published in the manuscript. Compared to just 10 years ago, there are now tremendous efforts in the rheumatologic community directed toward investigating treatments and outcome measures for Sjögren's."

A consensus expert panel (CEP) of 30 to 40 clinicians from academia and community practices, RNs, and patients used a modified Delphi process to review the draft guidelines. Proposed guidelines required a CEP agreement level of 75% for adoption.

Sjögren's: The Big, Unanswered Questions

Dr Matteson said, "Major issues include, for example, the classification and diagnosis of Sjögrens. In practice; many patients with dry mouth and dry eyes are diagnosed with Sjögren's even when other symptoms and laboratory findings are lacking, making it difficult to study the disease course or effect of various therapies.

The guidelines authors stress the need for an accepted standard for clinically meaningful improvement, both for clinical use and for research trial design.

Dr Carsons added, "We still require identification of effective pharmacologic therapies for prevention and treatment of the individual extraglandular manifestations of primary Sjögren's."

Development of the guidelines was supported by the Sjögren's Syndrome Foundation. Dr Carsons has received consultant fees from Biogen Idec. Other coauthors reported consultant fees from UCB, Biogen Laboratories, and Pfizer, and an immediate family member who owns stock in Amgen. Dr Matteson has disclosed no relevant financial relationships.

Arthritis Care Res. Published online July 7, 2016. Abstract

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