Psoriatic Arthritis: A Look Back at Moll & Wright’s Landmark 1973 Paper

One of the paper’s most important and enduring contributions was the elucidation of disease definitions and detailed disease subtypes. In their paper, Moll and Wright pointed out there was no good existing definition of psoriatic arthritis in the medical literature. They discussed the wide spectrum of definitions being used, all of which they considered too specific. Instead, Moll and Wright adopted a broad definition of psoriatic arthritis: Psoriasis associated with inflammatory arthritis (peripheral and/or sacroiliitis or spondylitis), “usually with a negative serological test for rheumatoid factor.”¹

This was not just an academic exercise. “In order to define a disease, you really need a case definition,” says Dr. Ritchlin. “In this paper, they put together the case definition of what it is to have psoriatic arthritis.”

In addition to this, the team provided a detailed description of the various clinical presentations of the disease, which included some more specific features, such as dactylitis. They wrote, “The classical picture of psoriatic arthritis having a predilection for the [distal interphalangeal joints] should be revised. It is clear from more extensive clinical surveys that a variety of presentations ranging from single ‘sausage’ digits to arthritis mutilans may be observed.”¹

In 1959, in an earlier publication, Dr. Wright had proposed three subcategories: predominant distal interphalangeal disease, severely deforming arthritis (which included those with axial disease) and rheumatoid-like disease.⁶ In this paper, the team revised this earlier characterization to describe five broad clinical groups of psoriatic arthritis: predominant distal interphalangeal joint disease, asymmetrical oligoarthritis, symmetrical polyarthritis (which might resemble rheumatoid arthritis in appearance), spondylitis and arthritis mutilans.¹

In so doing, the team acknowledged that “There is often no clear division between one type of presentation and another.” They also noted that peripheral joints may also be involved in a case of predominant spondylitis and that patients with arthritis mutilans also often had sacroiliitis. In other words, a degree of fluidity between these presentations often existed.¹

“They really took all of these earlier reports and distilled them into these subgroups. Those were really helpful for clinicians in thinking about diagnosis, and in some cases really helping [us] understand clear differences between other forms of arthritis—[such as] rheumatoid arthritis,” says Dr. Ritchlin. “They were able to [give] a case definition and go into great detail on the heterogeneity and the characteristics of those subsets.”

Some later researchers have proposed modifications to these subtypes in terms of disease classification, although Dr. Ritchlin believes these subtype descriptions have held up fairly well over time.⁷ “What we do see is a lot less arthritis mutilans than we did, and we don’t know why,” he adds.

Whether these subcategories represent distinct, but overlapping, pathophysiologies is unknown. It does appear the association of the B27 human leukocyte antigen (HLA) haplotype may be stronger for the predominantly spondylitis form than for other subtypes.⁸ But in terms of current treatment guidelines, distinctions between severe and/or treatment-resistant disease compared with less severe disease are much more important than the particular subtype presentation.⁹

Broader Context

The period was a fruitful one for psoriatic arthritis more broadly. Earlier evidence provided by Moll and others had suggested a genetic contribution to the disease that was likely multifactorial in nature.¹

In another 1973 paper, Moll and Wright published a family study of over 100 probands with psoriatic arthritis and over 300 of their relatives.¹⁰ The results bolstered their earlier conclusion that psoriatic arthritis is a disease in and of itself, and confirmed previous reported linkages between psoriatic arthritis and ankylosing spondylitis. It also suggested genetic factors were involved in the disease etiology.

Notes Dr. Ritchlin, “They were among the first to report that this is a highly familial, inherited disease.”

“What is really interesting is that in 1973, the year both [Moll and Wright] papers came out, a group at UCLA reported the HLA-B27 association with ankylosing spondylitis in the New England Journal of Medicine,” Dr. Ritchlin continues.¹¹ “This was really a banner year for spondyloarthropathies. That paper came out, and then a second paper on HLA-B27 came out from a group in England on ankylosing spondylitis.”¹² These key papers helped further establish the genetic nature of the disease underlying its distinctive pathophysiological nature.

Moll and Wright’s major contributions extended beyond psoriatic arthritis into other forms of seronegative arthritis. In 1974, the pair published another seminal paper, this one describing the seronegative arthritis group and systematically itemizing their similarities and distinctions: “Associations Between Ankylosing Spondylitis, Psoriatic Arthritis, Reiter’s Disease, the Intestinal Arthropathies, and Behçet’s Syndrome.”¹³ Here they identified “an interesting group of non-rheumatoid disorders in which striking clinical and familial inter-relationships can be demonstrated.”

As Dr. Ritchlin relates, “Moll and Wright worked together for quite a long time. I would say this is an apogee of their work, this paper on psoriatic arthritis and the one on the family of spondyloarthropathies published the following year. These two years were really incredibly important in terms of unveiling the group of spondyloarthropathies and their clinical and genetic similarities.”

Gradual Recognition

Although Moll and Wright’s paper helped solidify the concept of psoriatic arthritis in the medical literature, some hesitancy persisted. This remaining resistance impeded future research and slowed the progression of knowledge about the disease. At the time, much less research was being performed on psoriatic arthritis than on other arthropathies, especially rheumatoid arthritis and ankylosing spondylitis.¹⁴

For example, in the mid-1970s, Dr. Espinoza and colleagues attempted but failed to obtain research funding for psoriatic arthritis from both the Canadian Rheumatology Society and the U.S. National Institutes of Health. Dr. Espinoza says, “According to grant reviewers, the main reason given for rejection was that psoriatic arthritis was not considered a distinct disorder and that most likely it was rheumatoid arthritis in patients with psoriasis.” He adds that Moll and Wright’s 1973 paper and later publications building on this work helped provide the evidence to eventually dispel that belief.

But this transition took time. Dr. Ritchlin describes the research in psoriatic arthritis he began in 1992. “There was little research going on in the field at that time, so we’re talking 20 years later. It was still pretty much a wide-open territory. It wasn’t until the late ’90s or early 2000s that things started to take off. That’s when we recognized that tumor necrosis factor was important in this disease, and we saw the first phase 2 trials showing it was very effective in psoriatic arthritis. Now it’s very clear that these diseases are very different from both the mechanistic and therapeutic point of view.”

Continuing Diagnostic Challenges

In their 1973 paper, Moll and Wright described many diagnostic problems that still challenge physicians, because no clear biomarker of the disease has yet been found. For example, they wrote, “A point that has been insufficiently stressed is the frequency with which patients are unaware that they have psoriasis and also the frequency with which minimal psoriasis in ‘hidden’ areas (scalp, natal cleft, perineum, and umbilicus) remains undetected by the clinician. Often, the only manifestation of the rash is a tiny patch either in one of these hidden areas or in one of the classical sites (back of the elbow or front of the knee).” They also noted that it is important for clinicians to realize nail involvement may be the only apparent manifestation of psoriasis.¹

The pair discussed some of the challenges in distinguishing psoriatic arthritis from osteoarthritis, Reiter’s disease, osteoarthritis, traumatic arthritis and rheumatoid arthritis. The latter, in particular, remains a challenge to this day. Dr. Espinoza notes, “In patients with polyarticular involvement and disease duration longer than five to 10 years, it is often difficult to distinguish the disease from rheumatoid arthritis.”

Dr. Ritchlin acknowledges that diagnosis is sometimes fluid. “Sometimes you’ll diagnose a patient with seronegative rheumatoid arthritis, and then, over time, it becomes apparent they have psoriatic arthritis, after they develop psoriasis or other features. Right now, the diagnosis is totally based on clinical characteristics, which can be very complicated and subtle.”

Yet it is important to get the correct diagnosis as soon as possible, Dr. Ritchlin notes, because some therapies are more effective than others (see “Rheumatology Drugs at a Glance, Part 1: Psoriatic Arthritis,” The Rheumatologist, April). “The crossover is anti-TNF agents and methotrexate. But in terms of the biologics, there are some very big differences, particularly with drugs like rituximab, IL-6 receptor antagonists like [tocilizumab], which are more effective for RA, and the anti-IL-17 drugs, which work for psoriatic arthritis but not for RA.”

The hunt is on for a serum biomarker that may be used to more easily diagnose psoriatic arthritis. New biomarkers are under development, but this process is time consuming and challenging. Notes Dr. Ritchlin, “The National Psoriasis Foundation is entertaining proposals for investigators to propose how to find a biomarker for this disease, and they are giving out a lot of money to do that.”

Until such a biomarker is found, clinicians will have to continue to rely on their clinical acumen and detailed knowledge of possible disease presentations.

Later Criteria

For the 30 years or so after their 1973 paper, almost all published studies of psoriatic arthritis used the criteria established by Moll and Wright: Psoriasis associated with inflammatory polyarthritis, usually with a negative serological test for rheumatoid factor.⁷ Moll and Wright seem to have designed their definition to be sensitive without being overly specific. However, some researchers believe that, in practice, Moll and Wright may have used other more specific disease features (such as dactylitis and enthesitis) to make their clinical diagnoses, even though these were not specifically included in their disease definition itself.⁷ In other words, Moll and Wright may have not intended for their definition to be used as strict clinical criteria in the modern sense.

Later researchers have sometimes differed in their interpretations of the definitions and clinical subgroup descriptions presented in Moll and Wright’s paper and may have over-interpreted the paper’s disease definition as an absolute criteria. Eventually, this led to some criticisms of what became known as the Moll and Wright criteria, and several attempts were made to establish other diagnostic criteria that could be expected to perform more reliably in clinical trials. These new criteria were developed to add specificity to the disease criteria, usually adding some feature that also resulted in reduced sensitivity.¹⁴

Dr. Espinoza and colleagues actually put forth one set of these new proposed criteria. “Together with Frank Vasey, my close associate and collaborator years back, we realized the inclusion of skin and/or nail involvement and imaging studies of sacroiliac joints would render any classification criteria more sensitive and specific,” he explains. “This assumption was proven correct years later, although we did not validate our proposed criteria.”

Eventually the CASPAR criteria were established in 2006, based on data from the Classification of Psoriatic Arthritis study group. According to CASPAR, to achieve a formal diagnosis of psoriatic arthritis a patient must exhibit inflammatory articular disease of the joint, spine or enthesis. In addition, patients must have at least three of the following:

1. Present or past psoriasis or family history of psoriasis (only one additional item is needed if the patient currently has psoriasis)¹⁵
2. Psoriatic nail dystrophy;
3. Current or past dactylitis;
4. Radiological evidence of psoriatic arthritis; and/or
5. Negative rheumatoid factor test.

Dr. Espinoza notes these criteria are now widely used both at the clinical level and for clinical trials. “CASPAR has been validated, and it performs well across ethnic groups, and in early and chronic disease. It meshes well with current therapeutic guidelines for psoriatic arthritis.”

Phase 3 trials currently require patients meet CASPAR criteria for inclusion. But Dr. Ritchlin draws a distinction between these types of criteria and looser diagnostic criteria. “They don’t equal diagnostic criteria, because diagnosis is really based on clinical judgment.”

In other words, a patient might have incomplete criteria via CASPAR for inclusion in a psoriatic arthritis trial, but enough characteristics for clinical diagnosis.

“When you are talking about diagnosis in a clinical setting, it’s more clinical judgment,” he adds. “Some people will use the CASPAR criteria. Some people will use the Moll and Wright, which is much broader, so if they see a patient with inflammatory arthritis and psoriasis, they may diagnosis them with psoriatic arthritis. Others may require the presence of dactylitis or X-ray changes. So it ranges across the spectrum as to how these patients are diagnosed.”

Although strict Moll and Wright criteria are no longer used in a research setting, the importance of their comprehensive disease description still stands out. The pair’s landmark clinical synthesis ultimately made possible further refinements, categorization and research progress on the disease.

Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.

References

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