Author: Claire Barnard
Challenges, guidelines, and research priorities
Psoriatic arthritis (PsA), a heterogeneous disease involving multiple domains, can be challenging to manage, particularly in resource-limited settings. With the majority of published research studies in PsA coming from resource-rich countries, guidelines from organizations including the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are not necessarily applicable to clinical practice in places such as Africa and Latin America, and do not address the unique challenges faced by rheumatologists and other healthcare providers (HCPs) caring for people with PsA in these resource-limited settings.
In early 2020, the International League of Associations for Rheumatology (ILAR) issued some recommendations for PsA management in resource-limited settings based on an adaptation of existing guidelines from GRAPPA and EULAR. The authors highlighted a dearth of evidence to address a number of clinically relevant questions, and proposed research priorities for these settings.
We speak to Vinod Chandran (University of Toronto, Ontario, Canada), lead author on the ILAR guidelines, to gain an understanding of the present issues, and explore some of the particular considerations in specific settings through conversations with specialists who have experience working with PsA patients in Latin America, India, and Africa. Broadly, the issues fall into four main categories:
- access to specialists;
- treatment availability;
- monitoring considerations; and
We also talk to the specialists about the ILAR guidelines, and the current and future research priorities in the different settings.
The issues: Access to specialists
“Resource is always limited wherever you go worldwide,” and this is “particularly acute in otherwise resource-poor settings,” says Chandran. He points out that delayed diagnosis represents an important issue, arising because PsA requires expert assessment, but there are relatively few rheumatologists in some resource-limited settings compared with other HCPs such as primary care physicians and internal medicine specialists.
“A lack of awareness of this condition” in some settings means that “diagnosis is either not made or made too late and so the outcomes are then poor,” he adds.
Lack of facilities
Ashish Mathew, a rheumatologist who is currently based at the University of Toronto and previously worked at the Christian Medical College in Vellore, India, says that from a patient’s perspective, “the major resource limitations [in India] would be facilities and finances.” He explains that India has “no system of general practitioners or family physicians,” and patients make appointments directly with a rheumatologist when they experience symptoms, with a wait of around 2–3 months in large centers.
“The Christian Medical College is one of the biggest tertiary care centers in the country, and we have patients coming from different parts of India,” with “a specific derm–rheum combined clinic once a week where we see patients with psoriasis and psoriatic arthritis,” he says.
Mathew adds that rheumatologist availability is limited, with an urban–rural divide; he estimates that there are less than 1000 trained rheumatologists for the Indian population of 1.3 billion, with fewer and fewer specialists as you go from cities to more rural areas. This results in other specialists treating rheumatology patients in some instances, with some patients visiting orthopedic surgeons in the first instance “because they are considered to be the musculoskeletal doctors.”
The issues: Treatment availability
Chandran says that following delayed diagnosis, access to treatment can represent a major problem for some patients with PsA in resource-limited settings.
“The [conventional] DMARDs methotrexate, sulfasalazine, [and] leflunomide are the most commonly used drugs [in many resource-limited settings],” even though “the evidence of efficacy in PsA is not that great.”
He adds that “when it comes to biologics, even the biosimilars that are available in many parts of the world are still quite expensive, and so access to biologics is almost impossible in the average patient from resource-poor settings.”
Our interviewees from South America, India, and Africa all agreed that access to treatment, particularly biologics, is a problem in these settings.
In Brazil, Penélope Palominos says that although a number of conventional DMARDs including methotrexate, sulfasalazine, cyclosporine, and leflunomide, as well as biologics such as tumor necrosis factor (TNF) inhibitors and interleukin (IL)-17A inhibitors, “are currently available in the public health system for treatment of PsA, there is a delay between the physician’s prescription and the patient’s receipt of the treatment.”
She points to a study published in 2019 showing that the median delay between the medical appointment and first dispensation of the prescribed drug for PsA was 66 days, with the largest delay due to “state proceedings, which include [the time between] requesting the drug until the authorization of treatments.”
“Patients with low educational and economic levels have difficulties obtaining all the documents required by the state and renewing the process every 6 months to receive their therapy,” she adds.
She notes that delays “in distributing the medicines from the capital to the smaller cities” in Brazil can contribute to problems with treatment access, with one study showing that limited drug access precluded treatment escalation in 18% of 78 patients who required escalation because they did not meet their treatment target of minimal disease activity.
The issues: Drug monitoring
Chandran says that the monitoring associated with drug treatment in PsA can be a problem too.
“Access to the drugs continues to be a problem, and when we [have patients] on these drugs we tend to request blood tests to monitor for toxicity, especially in the first few months, [but] lack of access to testing facilities, cost, and even the reliability of these labs are a problem,” he explains.
“So once in management, even using drugs that have been available for many years is a problem when you treat patients in resource-poor settings.”
The issues: Comorbidities
Another factor that can complicate the diagnosis and management of PsA in resource-limited settings is the presence of comorbidities.
“These comorbidities will be different in different parts of the world,” says Chandran.
Indeed, Penélope Palominos highlights that “in Brazil some regions have high prevalence of tuberculosis, Chagas disease, leishmaniosis, [and] leprosy,” and “the use of immunosuppressive therapy in regions where infectious diseases are prevalent is a challenge.”
On the other hand, Ashish Mathew says that India is currently in a “transitional phase” regarding comorbidities.
“There was a phase which was troubled with communicable diseases; there were a lot of infections [such as] tuberculosis and leprosy,” but nowadays “we’re battling with another whole set of comorbidities that are similar to [those in] the Western world, [such as] cardiovascular diseases [and] noncommunicable diseases, including diabetes,” he explains.
“India is supposed to be the world capital of diabetes.”
The ILAR guidelines
In an attempt to address some of the issues with managing PsA in resource-limited settings, particularly the Americas and Africa, Chandran and colleagues developed the ILAR guidelines, which were adapted from existing recommendations from GRAPPA and EULAR.
“The idea was to try to focus on data coming out from these countries, so that we can give more specific recommendations tailored to them, so based on data, rather than expert opinion,” he says.
“But unfortunately, given the lack of personnel, resources, and the huge clinical burden, there is really not much research coming out of these settings, so despite our extensive systematic review, focusing on databases from Africa and Latin America, we really didn’t get answers to our questions,” he said.
Therefore, Chandran and team’s guidelines were “based mostly on expert opinion,” and focus on principles such as treatment goals, which “would be similar wherever you are in the world” – involving treatment targets of remission or minimal disease activity, and the need to assess all the domains of PsA – as well as “shared decision making and managing appropriate follow up based on what is practical in that setting.
Chandran feels that “one of the criticisms [of the guidelines] would be that the recommendations don’t really tell you much [in addition to] what is already known.” However, “by putting [the topic] front and center, we’ve reminded everybody that this is an important disease to manage and there are unique problems in Africa and Latin America, primarily related to the access to therapy and associated infections and other comorbidities,” he says.
And Chandran believes that the most important outcome from the ILAR guidelines was a research agenda for resource-limited settings, “which hopefully will inspire people working in these areas to conduct studies […] so that these guidelines in future [can draw on] data from resource-poor settings, rather than just recommendations from [people who] have worked or are working in these areas.”
The research agenda
Chandran says that the research agenda for resource-limited settings includes many different avenues. Given the limited availability of rheumatologists in many countries, he thinks that one of the priorities should “be to try to evaluate patients treated by specialists versus internists [or] other general practitioners and see if their long-term outcomes are any different.”
Other important questions include “how frequently should we monitor?” and “how cost-effective is screening?” as well as the most appropriate combination therapy to use in countries with limited choice, he says.
Patients in resource-limited settings are often given “methotrexate [in combination with] leflunomide, methotrexate with sulfasalazine, [but] such combination therapy has not been really tested in clinical trials, and the safety is not really well known,” he says.
“People tend to borrow data from rheumatoid arthritis, [including on] management or combination therapies [and] standard of care, and we need to do more [studies] in psoriatic disease, especially in countries where the prevalence of infections and comorbidities is high, especially in diabetes and liver dysfunction.”
And in light of the comorbidity profile in many resource-limited settings, he says that further work is needed to establish how to screen for infections, as well as to learn how the treatment of these infections impacts PsA and vice versa.
“These questions have come to the forefront in Europe and North America because of COVID-19,” but “similar questions have always existed in resource-poor settings where there’s a lot of exposure to infections that we generally don’t see here in North America,” he stresses.
Infections, epidemiology, and treatment responses
Ajesh Maharaj says that better understanding of the interplay between PsA and infections, particularly HIV, is a key research priority in Africa.
“It is known that once patients with PsA develop HIV, the disease becomes worse,” but it is not known why, he says. “We need more research; the research agenda [in Africa] needs to be extended to HIV and PsA, rather than looking at these two different diseases in isolation.”
Maharaj believes that another key research priority in Africa is epidemiology. “We desperately need epidemiological studies in South Africa in particular and in Africa in general,” he stresses. Maharaj notes that there is a dearth of such studies in Africa, which could be partially attributed to a very low prevalence of psoriasis and PsA in the African population, the reasons for which are “not clearly understood and [have] not been studied previously.” This low prevalence could be due to genetics, he speculates, and believes it is important to investigate “whether these African populations have either the presence of a preventative gene, or a lack of susceptibility genes.”
And finally, Maharaj says that an important research question in the African setting is: “what are the local responses to available therapy and how do they differ from the responses in patients overseas?”
“I think these are very, very important research priorities that need to be put in place, and […] we need to take this research agenda forward in collaboration with our colleagues in Europe and in North America.”
Overcoming the barriers to research
Despite there being a great need for research into various aspects of PsA in settings like Africa, Latin America, and India, limited research funding remains a problem.
Chandran thinks that “for biologic therapy [and] more advanced therapies, the research is going to go on,” but “many of the questions that we really need to answer are not being answered because there is no interest from the pharmaceutical industry.”
Therefore, “investigators in both GRAPPA and other agencies [need to work] with investigators in resource-poor settings to actually answer questions which may not be of interest to pharmaceuticals, but are quite important for day-to-day practice in these cases.”
He hopes that “with this research agenda, and also getting people from many countries in Latin America and Africa together, as one group, we could inspire more research,” which is “ultimately what we would like to get.”
Despite the limited funding, Chandran points out that “one thing about India or Latin America or Africa is there are a lot of patients who are there, and many of them would participate in clinical research, and so many of these studies can actually be done rather quickly and the cost would not be that enormous.”
“I’m hoping that [the ILAR] guidelines do the job of getting the message out there to connect researchers, and focus on answering questions from resource poor settings,” he says.