Mixed connective tissue disease sjogren syndrome PMR

1. MULTIPLE
CONNECTIVETISSUE
DISEASE
BY – KARTHIKEYAN

2. Introduction
• Mixed connective tissue disease (MCTD) is a rare systemic autoimmune
disease with an overlapping feature of at least two connective tissue diseases
(CTD), including systemic lupus erythematosus (SLE), systemic sclerosis
(SSc), polymyositis (PM), dermatomyositis (DM) and rheumatoid arthritis
(RA) along with the presence of a distinctive antibody, anti-U1-
ribonucleoprotein (RNP)

3. Etiology
• The etiology of mixed connective tissue disease is unclear. No clear risk
factor has been identified so far. Immune activation due to environmental
factors in people with genetic predisposition is thought to play a role.
• The incidence of MCTD was 1.9 per 100,000 adults per year. The mean age
of diagnosis was 48 years, and 84% of affected populations were females.
• Affects all races, and its clinical manifestations are similar in all ethnic
groups.

4. Pathophysiology
• Since the anti-U1-RNP antibody is the hallmark of mixed connective tissue disease,
the assumption is that anti-U1-RNP and its antigen play a role in the pathogenesis of
MCTD.
• U1-RNP complex is an intranuclear protein that converts pre mRNA to mature RNA.
It constitutes three specific proteins A, C, and 70kDa, to which anti-U1 RNP
antibodies bind.
• 70kDa antigen is the main target of the anti-RNP antibody in MCTD.The genetic
association of MCTD with HLA-DR4 and DR2 phenotypes indicates the
involvement of T cell receptors and HLA molecules in the generation of anti-U1-
RNP.

5. Causes
• Initial symptoms of mixed connective tissue disease are usually non-specific and include
arthralgia, malaise, myalgia, and low-grade fever. Almost any organ system can be affected by
MCTD.
• Skin: The most common skin change is the Raynaud phenomenon, which is also the most
common presenting feature of MCTD. Hand edema, atherosclerosis, calcinosis cutis,
telangiectasia, erythema nodosum, hair loss, and vasculitis of digits are other manifestations.
Discoid plaques and a malar rash similar to SLE can also occur. Nailfold changes are visible
by capillary microscopy.
• Joint: Joint involvement is usually more severe than in SLE. Arthritis with deformities similar
to RA can also occur. Arthritis mutilans resembling psoriatic arthritis are rarely present.
• Muscle: Inflammatory myopathy clinically and histologically similar to polymyositis often
manifests as myalgia and is a common symptom of MCTD. Rarely myositis can also be the
initial presentation.

6. • Lung: Pulmonary involvement occurs in almost 73% of patients, and dyspnea is the
most common symptom. Patients can also be asymptomatic until fatal consequences
arise. Other symptoms include cough, pleuritic chest pain, wheezing, and
hemoptysis. Pulmonary manifestations may include pleural effusion, pulmonary
arterial hypertension, interstitial lung disease (ILD), pulmonary vasculitis,
thromboembolic disease, alveolar hemorrhage, infections, and obstructive airway
disease.
• Heart: Pericarditis is the most common variant of cardiac disease involving up to
40% of patients. Pericardial effusion, mitral valve prolapse, myocarditis, accelerated
atherosclerosis, and conduction abnormalities can also occur.
• Kidney: Renal involvement occurs in 15 to 25% of MCTD patients. Most patients
are usually asymptomatic. Membranous nephropathy is the most common finding.
Nephropathy can sometimes be associated with significant morbidity, risk of
hypertension, and chronic kidney disease, often requiring dialysis.

7. • The central nervous system(CNS): Though the lack of CNS involvement is
characteristic of MCTD, mild involvement has been described in about 25% of
patients. Trigeminal neuralgia is the most common CNS manifestation. Psychosis,
convulsion, peripheral neuropathy, headache, nuchal rigidity, aseptic meningitis, and
sensorineural hearing loss can also occur.
• Gastrointestinal tract: Esophageal hypomotility, dilatation, and GERD are frequent
features. Less common manifestations are pancreatitis, megacolon, duodenal
bleeding, portal hypertension, and autoimmune hepatitis. Rarely patients can present
with protein-losing enteropathy. They often have anasarca due to hypoproteinemia.
• Hematological involvement: Anemia and leukopenia are common, while there are
also reports of thrombocytopenia.

9. DIAGNOSIS
• Complete blood cell count (CBC)
• Urinalysis
• Routine blood chemistry
• Indicators of acute phase response (erythrocyte sedimentation rate [ESR] or
C-reactive protein [CRP])
• Muscle enzymes if myositis is suspected clinically
• Antinuclear antibodies
• Anti–U1-ribonucleoprotein (RNP) antibodies

11. Criteria
• The Alarcón-Segovia diagnostic criteria consist of a positive anti–U1 RNP
titer (>1:1600) and at least three of the following five clinical findings :
• Hand edema
• Synovitis
• Biologically or histologically proven myositis
• Raynaud phenomenon
• Acrosclerosis with or without proximal systemic sclerosis

12. Treatment
• No randomized controlled trials to guide the treatment of mixed connective tissue disease
have yet taken place. The goal of therapy is to control symptoms and is directed by clinical
manifestations and organ involvement.
• Raynaud phenomenon: Symptomatic management includes avoiding caffeine, smoking,
cold temperature, and injuries. Oral calcium channel blockers (CCB), e.g., nifedipine which
decreases peripheral resistance, are an option. Intravenous prostaglandins and topical
nitroglycerins are effective. Case reports exist of the Raynaud phenomenon responding to
rituximab.
• Arthritis and arthralgia usually respond to NSAIDs and hydroxychloroquine. For refractory
synovitis, corticosteroids and methotrexate can be used.
• Pleuritis, pericarditis, myositis, myocarditis, and aseptic meningitis usually respond to
steroids. Steroid-sparing agents, e.g., methotrexate, cyclosporine, azathioprine, and
mycophenolate mofetil, are commonly used as second-line agents. Steroid-resistant
myositis may respond to intravenous immunoglobulin.

13. • Pulmonary hypertension is usually less responsive to steroids. Patients who
respond to a vasodilator challenge during right heart catheterization receive
treatment with CCB. Prostaglandins (epoprostenol), endothelin receptor
antagonists (ambrisentan), phosphodiesterase 5 inhibitors (sildenafil),
immunosuppression with corticosteroids and cyclophosphamide are all
therapeutic considerations.
• Esophageal disorders also respond to steroids. Gastroesophageal reflux disease
(GERD) treatment is with proton pump inhibitors (PPI), lifestyle, and dietary
modification, e.g., elevating the head of the bed and avoiding dietary triggers.
Prokinetics and gastric fundoplication are possible options for those who fail
twice-daily PPI therapy. Esophageal motility disorder requires prokinetics.
Patients with malabsorption should be on a lactose-free diet, and medium-chain
triglycerides should substitute for long-chain fatty acids.
• Autoimmune hemolytic anemia and thrombocytopenia receive initial treatment
with steroids. Clinicians can consider rituximab in resistant cases.

14. Differential Diagnosis
• Due to the presence of nonspecific symptoms and different organ involvement, MCTD mimics
several other conditions, especially CTD. A few differential diagnoses are listed below.
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Polymyositis
• Dermatomyositis
• Scleroderma
• Bacterial infections
• Idiopathic pulmonary arterial hypertension

15. Prognosis
• Almost one-third of patients with MCTD undergo complete resolution, while another
third can develop life-threatening complications.
• The mortality rate varies between 8 and 36%.
• Pulmonary hypertension is the most common cause of death. Interstitial lung disease,
infections, cardiovascular diseases, and malignancies are other causes.The presence of
IgG anticardiolipin antibodies might be associated with severe disease.
• Patients with MCTD can clinically progress to other CTD, e.g., SSc, RA, Sjogren
syndrome, and systemic lupus erythematosus. On the other hand, patients with other
CTD or undifferentiated CTD can eventually develop into MCTD.

16. Complications
• Renal crisis, malignant hypertension, and respiratory failure secondary to
pulmonary hypertension, can occur rarely.
• Cardiovascular complications include dilated cardiomyopathy, cardiac
tamponade, coronary sclerosis with ischemic cardiomyopathy, and
arrhythmias.

17. Sjogren syndrome
• Sjögren syndrome is a long-term autoimmune disease that affects
the body's moisture-producing glands (lacrimal and salivary)
XEROPHTHTMALMIA, XEROSTOMIA and often seriously affects
other organ systems, such as the lungs, kidneys, and nervous system.
• Women are most affected at ages 40 to 50
• An increase of more than 50% in newly diagnosed primary Sjögren
syndrome was reported in Brazil during 2020, with more cases
reported during the months following the first wave of COVID-19 cases

18. Types
• Primary sjogren syndrome – SICCA SYNDROME only moisture producing
gland affected. No other autoimmune disease present.
• Secondary syndrome – presence of another autoimmune disease in addition
to sjogren syndrome
• 15% with RA and 30% with SLE experience sjogren syndrome

19. Pathophysiology
• a combination of this genetic predisposition and environmental triggers (i.e., viral or bacterial
infection) cause Sjögren's syndrome to develop.
• number of genes have been identified that are thought to play a role in the development of
this syndrome; these include various forms of the HLA-DRB , HLA-DQA, and HLA-
DQB genotypes.
• Salivary and lacrimal glands are infiltrated by the T cells. This infiltration leads to the release
of cytokines and the resultant inflammation and destruction. The B cells produce
autoantibodies, SSA (anti-Ro) and SSB (anti-La), which are associated with Sjögren's
syndrome.

22. Diagnosis
• Schirmers test
• Sialometry – test salivary flow
• Blood test to indicate antibody anti ssa ssb autoantibody
• Lip biopsy

25. PROGNOSIS
• Among patients with Sjögren syndrome, the incidence of non-Hodgkin
lymphoma is 4.3% . The mean time to the development of non-Hodgkin
lymphoma after the onset of Sjögren syndrome is 7.5 years.
• The most common histologic subtype of non-Hodgkin lymphoma in Sjögren
syndrome is mucosa-associated lymphoid tissue (MALT) lymphoma, which
can develop in any nonlymphoid tissue infiltrated by periepithelial lymphoid
tissue—most commonly the salivary glands, but also the stomach,
nasopharynx, skin, liver, kidneys, and lungs. The progression of these
infiltrates to lymphoma occurs slowly and in a stepwise fashion. Lymphoma
is present at more than 1 site in 20% of patients at initial diagnosis.

26. COMPLICATION
• Children born to mothers with antibodies against SSA/Ro and SSB/La
are at an increased risk of neonatal lupus and congenital heart block.
• antiphospholipid syndrome - increased fetal wastage and vascular
thromboses

27. Polymyalgia rheumatica
• Polymyalgia rheumatica (PMR) is a condition that causes pain,
stiffness and inflammation in the muscles around the shoulders, neck
and hips. morning stiffness that lasts for more than 1
hour.Approximately 15% of patients with PMR develop giant cell
arteritis (GCA)

28. Etiology
• PMR is associated with the HLA-DR4 haplotype. A high level of IL-6 is
associated with increased disease activity.
• PMR has been reported as a rare complication of cancer therapy with
immune checkpoint inhibitors (eg, nivolumab).
• Onset and recurrence of PMR has been reported shortly after viral
infections (eg, influenza) and vaccinations, including COVID-19
vaccination

29. Pathophysiology
• Pathologically, GCA and PMR are similar, except that significant vascular
involvement does not occur in pure PMR. Synovitis, bursitis, and
tenosynovitis around the joints, especially the shoulders, hips, knees,
metacarpal phalangeal joints, and wrists, are seen in PMR.
• Systemic macrophage and T-cell activation are characteristic of both GCA
and PMR. Patients often have an elevated IL-6 level, which is likely
responsible for the systemic inflammatory response in both GCA and PMR.
Most studies in PMR show that a decrease in the level of circulating IL-6
correlates with remission of clinical symptoms.

30. • plasma concentrations of IL-6, IL-8, TNF-α, and IL-4 peaked between 4
and 8 am in both untreated patients and controls, although levels of those
cytokines were higher throughout the day in patients.

31. Diagnosis
• Rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies (anti-CCP)
• C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR)
• Complete blood cell count (CBC) with differential
• Blood glucose
• Serum creatinine
• Liver function tests
• Bone profile (including calcium and alkaline phosphatase)
• Dipstick urinalysis

33. TREATMENT
• Glucocorticoids are the preferred treatment.
• Short-term NSAIDs and/or analgesics may be used to treat pain related to comorbid
conditions such as osteoarthritis.
• Initial glucocorticoid therapy should be 12.5-25 mg/day of prednisone or the
equivalent.
• Intramuscular methylprednisolone may be considered as an alternative to oral
glucocorticoid therapy.
• Early introduction of methotrexate (MTX) in addition to glucocorticoid therapy, is
conditionally recommended for patients at high risk of relapse and/or prolonged
therapy, as well as in those with risk factors for adverse effects of glucocorticoid
therapy.
• Use of MTX may be considered during follow-up in patients with a relapse, lack of a
significant response to glucocorticoid therapy, or development of

34. • the target dosages for tapering are 10 mg/day of prednisone or the
equivalent within 4-8 weeks.
• If relapse occurs, increase the pre-relapse dosage and decrease
gradually (within 4-8 weeks) to the dosage at which the relapse
occurred.
• Once remission of PMR is achieved, taper the dosage by 1 mg every
4 weeks (or by 1.25-mg decrements using schedules such as 10/7.5
mg on alternate days) until treatment is discontinued.

35. THANKYOU