The enigma of mixed connective tissue disease—challenges in routine care

Abstract

Objectives As a rare and heterogeneous disease, mixed connective tissue disease (MCTD) represents a challenge. Herein, we aimed to unravel potential pitfalls including correct referral diagnosis, distinction from other connective tissue diseases (CTD) and treatment modalities. Methods We characterised the MCTD cohort at our tertiary referral centre. All patients were evaluated for fulfilment of classification criteria of various CTDs. SLEDAI-2 K and EUSTAR-AI were used in accordance with previous research to evaluate disease activity and treatment response. Results Out of 85 patients initially referred as MCTD, only one-third (33/85, 39%) fulfilled the diagnostic MCTD criteria and the other patients had undifferentiated CTD (16/85, 19%), non-MCTD overlap syndromes (11/85, 13%) and other rheumatic diseases. In our final cohort of 33 MCTD patients, 16 (48%) also met the diagnostic criteria of systemic sclerosis, 13 (39%) these of systemic lupus erythematosus, 6 (18%) these of rheumatoid arthritis and 3 (9%) these of primary myositis. Management of MCTD required immunomodulating combination therapy in most cases (15/28, 54%), whereas monotherapy was less frequent (10/28, 36%), and only a few (3/28, 11%) remained without immune modulators until the end of the follow-up period. Treatment led to a significant decline in disease activity. Conclusions Our study showed a high risk for misdiagnosis for patients with MCTD. As a multi-organ disease, MCTD required prolonged immunomodulating therapy to achieve remission. The establishment of an international registry with longitudinal data from observational multi-centre cohorts might represent a first step to address the many unmet needs of MCTD. Key Points• This cohort study aimed to identify challenges in the highly complex management of MCTD.• Clinical presentation of MCTD significantly overlaps with that of other CTDs, leading to a high risk of misdiagnosis.• Manifestations of MCTD are highly variable and potentially life-threatening, requiring continued immunomodulating treatment in most cases.• A composite score based on SLEDAI-2 K and EUSTAR-AI measures could represent an easy applicable tool to monitor disease activity and treatment response.

Acute Peritonitis Is Not Always a Surgical Fix: A Rare Case of Mixed Connective Tissue Disease Presenting as Polyserositis

“…The Alarcon-Segovia criteria are often used to aid in the diagnosis of MCTD, but there is currently no tool to measure disease activity [ 1 , 5 ]. As MCTD is a heterogeneous disease with nonspecific symptoms, it is estimated that only 10-33% of patients will fulfill the Alarcon-Segovia criteria at the time their first symptom appears [ 1 , 2 ]. In fact, many patients will only have one predominant symptom for up to 10 years prior to diagnosis, and 90% of patients are diagnosed with other conditions first [ 1 , 2 , 4 ].…”

“…As MCTD is a heterogeneous disease with nonspecific symptoms, it is estimated that only 10-33% of patients will fulfill the Alarcon-Segovia criteria at the time their first symptom appears [ 1 , 2 ]. In fact, many patients will only have one predominant symptom for up to 10 years prior to diagnosis, and 90% of patients are diagnosed with other conditions first [ 1 , 2 , 4 ]. Prior studies have shown that Raynaud’s phenomenon is the most common presenting symptom, but symmetric arthralgias are the most predominant symptom by the time patients fulfill the Alarcon-Segovia criteria [ 1 , 2 , 4 ].…”

“…Mixed connective tissue disease (MCTD) is a rheumatological autoimmune disease, also known as Sharp’s syndrome [ 1 , 2 ]. The disease is characterized by an array of non-specific systemic symptoms that overlap with those of other autoimmune diseases, such as systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), and/or polymyositis, and thus, the main diagnostic feature is the presence of autoantibodies called anti-U1 ribonucleoprotein (RNP) [ 1 ].…”

“…Human leukocyte antigen (HLA) molecules and T-cell receptors generate anti-U1-RNP complexes, and thus genetics and inflammatory cascades play a major role in the pathogenesis; however, ultimately, the cause is unknown [ 3 ]. MCTD occurs mostly in females between the ages of 30 and 39 years old, with women between the ages of 50 and 65 following close behind [ 1 , 2 ]. There are limited data regarding the epidemiology of MCTD and it is likely underreported, but a nationwide study from Norway in 2011 reported a prevalence of 3.8 per 100,000 adults and an incidence of 2.1 million patients diagnosed annually [ 1 ].…”

“…Although MCTD affects all races and the clinical manifestations are not different based on ethnicity, the manifestations of MCTD are very broad and non-specific [ 3 ]. It is debated as to whether MCTD is a separate phenomenon or if the disease is an early phase of another autoimmune disease that becomes more apparent over time [ 2 ]. This is because particular features are likely to appear first, such as Raynaud’s syndrome, arthritis, and puffy hands, whereas other symptoms, such as sclerodactyly, motility disorders, and interstitial lung disease appear much later [ 1 ].…”