‘The most challenging disease’: Misdiagnoses, unmet needs abound in systemic sclerosis
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Systemic sclerosis is the most challenging diagnosis to make among rheumatic and autoimmune conditions, according to 91% of respondents in a market analysis from Spherix Global Insights.
“I agree with the survey responses in that the rheumatologists highlighted systemic sclerosis as the most challenging diagnosis and the most challenging disease to manage in practice,” Dinesh Khanna, MD, MSc, professor of rheumatology and director of the Scleroderma Program at the University of Michigan, told Healio in an interview.
According to Khanna, who was not involved with the Spherix analysis, the difficulties with diagnosing SSc often begin before a rheumatologist is even involved.
“At the primary care level, there is lack of in-depth knowledge about SSc due to the rarity of the disease,” he said. “It is marked by nonspecific findings such as pain, fatigue, weight loss and Raynaud’s phenomenon during initial presentation. Even the initial signs of SSc are nonspecific. They may include joint swelling, puffy fingers, joint tenderness or carpal tunnel syndrome.”
Meanwhile, structural issues, including a lack of availability of specialized assessment tools, such as SSc-specific autoantibody testing, microvascular diagnostic testing — for example, nail fold capillaroscopy — can also disrupt diagnosis at the primary care level, Khanna said.
However, the difficulties presented by SSc are not limited solely to primary care.
“For rheumatologists, the key challenges include lack of effective and approved therapies and the multisystem and heterogeneous involvement of SSc,” Khanna said. “This makes it challenging to perform in-depth assessments in rare disease. As a result, there is significant morbidity and mortality.”
‘Clinch the diagnosis’
The researchers behind the Spherix market analysis surveyed 100 rheumatologists with clinical experience with SSc about the components of a diagnostic workup for the disease. More than 90% of respondents suggested that a clinical workup is very important, while approximately 80% each noted the importance of anti-Scl-70 and anti-centromere antibodies, as well as pulmonary function tests. Patient-reported symptoms and medical history were important for 76% of respondents, while nearly 70% said that RNA polymerase III and imaging were necessary.
“I generally agree, although all patients should have ANA by immunofluorescence — rather than multiplex bead assays that are widely utilized since RNA polymerase 3 and other SSc-antibodies are not included in the bead assays — and anti-Scl-70, anti-centromere, as well as anti-RNA polymerase 3 antibodies,” Khanna said. “RNA polymerase 3 is common in early SSc.”
Most patients with RNA polymerase 3 present with puffy fingers with or without Raynaud’s disease and constitutional symptoms, according to Khanna.
“RNA polymerase 3 antibody is strongly associated with diffuse skin involvement and with rapid progression from disease onset to peak skin disease severity,” he said. “Approximately 60% of patients with early SSc have three of the aforementioned SSc-specific antibodies. A patient can have SSc with triple negative antibodies, meaning Scl-70, centromere, and RNA polymerase 3.”
Khanna suggested that clinical exam components should also be considered.
“Careful history to assess for the SSc specific symptoms, such as puffy hands, which are the most common non-RP symptom, as well as skin thickening, arthritis, gastrointestinal symptoms and new carpal tunnel syndrome, are essential,” he said.
A physical exam can also assess for skin color changes, according to Khanna.
“Digital pits can help clinch the diagnosis,” he said. “Assessing for the nailfold capillary abnormalities provides confidence in the diagnosis.”
Physicians armed with this specific knowledge of SSc presentation may have the tools to diagnose patients sooner.
‘Careful review’ can prevent diagnostic delays
Further data from the Spherix survey indicated that 87% of respondents believe there is a need for faster diagnoses of patients with SSc.
“Delayed diagnosis is associated due to rarity of the disease, non-specific initial findings, and a lack of knowledge or availability of SSc-autoantibodies, such as RNA polymerase 3, and devices to assess for nailfold capillaroscopy changes,” Khanna said. “The majority of patients tend to go to their primary care providers with symptoms of pain, Raynaud’s phenomenon, fatigue and other constitutional symptoms.”
In the primary care setting, ANA is generally performed via multiplex bead assays. However, patients tend to be ANA negative, according to Khanna.
“Only 50% of patients are ANA-positive by multiplex bead assays, while 95% are positive by immunofluorescence since many SSc autoantibodies are missing on multiplex bead panel,” he said.
Further complications follow when SSc is misdiagnosed as either lupus, RA, fibromyalgia, primary Raynaud’s or some other condition, according to findings from the Spherix report.
“While ANA positivity is seen in 95% of patients with SSc, it is also very common in other connective tissue diseases,” Khanna said.
Other common symptoms include puffy hands and arthritis, which can lead to an erroneous lupus or RA diagnosis.
“Lack of clear scleroderma-associated physical findings in early disease, such as progressive skin thickening, and associated pain, fatigue, and anxiety/depression leads to a diagnosis of fibromyalgia,” Khanna said.
Providers should also keep in mind that approximately 5% to 10% of the general population experiences Raynaud’s disease, according to Khanna.
“Lack of a diagnostic work up — such as SSc-specific antibodies and a lack of availability and/or expertise regarding nailfold capillary devices — leads to misdiagnosis of Raynaud’s syndrome,” he said.
Education that new onset Raynaud’s, particularly in individuals aged 30 years or older, along with puffy fingers combined with unexplained symptoms, requires careful workup with ANA testing by immunofluorescence and SSc-autoantibodies, according to Khanna.
“Careful review of the nailfold capillaries can also facilitate early diagnosis of SSc,” he said.
Once patients are diagnosed, clinicians are then tasked with the difficulties presented by SSc management.
‘Lack of drugs’
Data from the Spherix report suggest that more than half of patients with SSc are not optimally managed.
According to the rheumatologists who responded to the survey, just 35% of patients with SSc are “well-managed on current treatment,” while 34% are “achieving some success but results are not optimal.” Meanwhile, an additional 17% “likely need to be switched to a new treatment at next visit.”
“The current treatment of SSc is based on managing ongoing signs and symptoms,” Khanna said.
However, symptom management is only part of the battle.
“Unlike RA and other connective tissue diseases, there is lack of drugs that are disease modifying overall,” Khanna said. “The current treatment paradigm includes vasodilator therapies for vascular involvement and immunosuppressive and anti-fibrotics for fibrotic complications.”
FDA approvals for tocilizumab (Actemra, Genentech) and nintedanib (Ofev, Boehringer Ingelheim) in SSc-associated interstitial lung disease, as well as approved therapies for pulmonary arterial hypertension, have allowed for real progress in the management of SSc. However, no therapy is approved for the overall disease.
“In addition, current therapies have modest effects and face challenges with insurance approvals as they are not FDA approved therapies,” Khanna said.
With these obstacles in mind, Spherix queried respondents about unmet needs in SSc. Results showed that 96% of respondents reported an “extremely high” unmet need for treatments in this condition.
The survey can also help steer the way for researchers who hope to meet these unmet needs. The majority of respondents stressed that clinical data, efficacy in achieving remission, and overall safety are the most important product characteristics for pipeline agents in SSc.
“I agree that new therapies should lead to substantial improvements/stabilization of SSc signs and symptoms,” Khanna said.
Reference:
Spherix Market Dynamix: Systemic Sclerosis (US) Q4 2024. https://www.spherixglobalinsights.com/rheumatology/
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